List of phenyltropanes

Last updated

Phenyltropanes (PTs) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; and thusly the phenyl is attached direct to the tropane skeleton with no further spacer (therefore the name "phenyl"-tropane) that the cocaine benzoyloxy provided. The original purpose of which was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (since the methylated benzoate ester is essential to cocaine's blockage of sodium channels which cause topical anesthesia) while retaining stimulant function. [lower-alpha 1] These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's and Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile. [2] ) Certain phenyltropanes can even be used as a smoking cessation aid (c.f. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers (in this case the long form is either RTI-COC-n, for 'cocaine' "analog", or specifically RTI-4229-n of the subsequent numbers given below in this article) [lower-alpha 2] Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.

Contents

3D rendering of troparil; which comprises a privileged scaffold of among the phenyltropane class of compounds. Phenyltropane.gif
3D rendering of troparil; which comprises a privileged scaffold of among the phenyltropane class of compounds.
Troparil structure: c.f. U.S. patent 5,496,953 Troparil structure.png
Troparil structure: c.f. U.S. patent 5,496,953

2-Carboxymethyl esters (phenyl-methylecgonines)

Epibatropane containing a nitrogen heteroatom in the benzene ring formation. Epibati-tropane.svg
Epibatropane containing a nitrogen heteroatom in the benzene ring formation.
Tamagnan: SSRI, SERT = 17(pM) = 10 times the strength of paroxetine for 5HT. Tamagnan.png
Tamagnan: SSRI, SERT = 17(pM) = 10 times the strength of paroxetine for 5HT.
RTI-298 RTI-298.svg
RTI-298
(4'-)para-cis-propenyl-phenyl-methylecgonine. A rare SDRI compound with negligible NET affinity (>2,800.0nM displacement value for NET ligand) that retains significant DAT & SERT (15.0nM & 7.1nM) affinity. RTI-11W.svg
(4′-)para-cis-propenyl-phenyl-methylecgonine. A rare SDRI compound with negligible NET affinity (>2,800.0nM displacement value for NET ligand) that retains significant DAT & SERT (15.0nM & 7.1nM) affinity.
C2-C3 unsaturated (non-isomeric, neither a nor b orientated) 2-naphthyl-tropane Carroll 15.svg
C2-C3 unsaturated (non-isomeric, neither α nor β orientated) 2-naphthyl-tropane
1-naphthyl-tropane in its usual (comparably non-standard) boat formation of its tropane ring. Carroll 13.svg
1-naphthyl-tropane in its usual (comparably non-standard) boat formation of its tropane ring.

Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state. [5]

Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact. [lower-alpha 3] The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine. [lower-alpha 4]

Blank spacings within tables for omitted data use "no data", "?", "-" or "" interchangeably.

2β-carbmethoxy-3β-(4′-substituted phenyl)tropanes (IC50 values)
monohalogen halide-phenyltropanes (11a—11e) alkyl-, & alkenyl-phenyltropanes (11r—11x) alkynyl-phenyltropanes (11y & 11z)
Structure Phenyltropane 11a-bb.svg Short Name
i.e. Trivial IUPAC
(non-systematic) Name
(Singh's #)
R (para-substitution)
of benzene
DA
[3H]WIN 35428
IC50 nM
(Ki nM)
5HT
[3H]paroxetine
IC50 nM
(Ki nM)
NE
[3H]nisoxetine
IC50 nM
(Ki nM)
selectivity
5-HTT/DAT
selectivity
NET/DAT
cocaine
(benzoyloxytropane)
H102 ± 12
241 ± 18ɑ
1045 ± 89
112 ± 2b
3298 ± 293
160 ± 15c
10.2
0.5d
32.3
0.7e
Phenyltropane 11a - WIN 35065-2 - Troparil.svg (para-hydrogen)phenyltropane
WIN 35,065-2 (β-CPT [lower-alpha 5] ) Troparil
11a
H23 ± 5.0
49.8 ± 2.2ɑ
1962 ± 61
173 ± 13b
920 ± 73
37.2 ± 5.2c
85.3
3.5d
40.0
0.7e
Phenyltropane 11b - WIN 35428.svg para-fluorophenyltropane
WIN 35,428 (β-CFT [lower-alpha 6] )
11b
F 14 (15.7 ± 1.4)
22.9 ± 0.4ɑ
156 (810 ± 59)
100 ± 13b
85 (835 ± 45)
38.6 ± 9.9c
51.6
4.4d
53.2
1.7e
Phenyltropane 11k.svg para-nitrophenyltropane
11k
NO2 10.1 ± 0.10????
Phenyltropane 11j.svg para-aminophenyltropane
RTI-29 [6]
11j
NH2 9.8
24.8 ± 1.3g
5110151521.415.4
Phenyltropane 11c.svg para-chlorophenyltropane
RTI-31
11c
Cl 1.12 ± 0.06
3.68 ± 0.09ɑ
44.5 ± 1.3
5.00 ± 0.05b
37 ± 2.1
5.86 ± 0.67c
39.7
1.3d
33.0
1.7e
Phenyltropane 11f.svg para-methylphenyltropane
RTI-32 Tolpane
11f
Me 1.71 ± 0.30
7.02 ± 0.30ɑ
240 ± 27
19.38 ± 0.65b
60 ± 0.53e
8.42 ± 1.53c
140
2.8d
35.1
1.2e
Phenyltropane 11d.svg para-bromophenyltropane
RTI-51 Bromopane
11d
Br 1.81 (1.69) ± 0.3010.6 ± 0.2437.4 ± 5.25.820.7
Phenyltropane 11e - RTI-55.svg para-iodophenyltropane
RTI-55 (β-CIT) Iometopane
11e
I 1.26 ± 0.04
1.96 ± 0.09ɑ
4.21 ± 0.3
1.74 ± 0.23b
36 ± 2.7
7.51 ± 0.82c
3.3
0.9d
28.6
3.8e
Phenyltropane 11h.svg para-hydroxyphenyltropane
11h
OH 12.1 ± 0.86
Phenyltropane 11i.svg para-methoxyphenyltropane
11i
OCH3 8.14 ± 1.3
Phenyltropane 11l.svg para-azidophenyltropane
11l
N3 2.12 ± 0.13
Phenyltropane 11m.svg para-trifluoromethylphenyltropane
11m
CF3 13.1 ± 2.2
Phenyltropane 11n.svg para-acetylaminophenyltropane
11n
NHCOCH3 64.2 ± 2.6
Phenyltropane 11o.svg para-propionylaminophenyltropane
11o
NHCOC2H5121 ± 2.7
Phenyltropane 11p.svg para-ethoxycarbonylaminophenyltropane
11p
NHCO2C3H5316 ± 48
Phenyltropane 11q.svg para-trimethylstannylphenyltropane
11q
Sn(CH3)3144 ± 37
Phenyltropane 11g.svg para-ethylphenyltropane
RTI-83
11g
Et 55 ± 2.128.4 ± 3.8
(2.58 ± 3.5)
4030 (3910) ± 381
(2360 ± 230)
0.573.3
Phenyltropane 11r.svg para-n-propylphenyltropane
RTI-282 i
11r
n-C3H768.5 ± 7.170.4 ± 4.13920 ± 1301.057.2
Phenyltropane 11s.svg para-isopropylphenyltropane
11s
CH(CH3)2 597 ± 52191 ± 9.575000 ± 58200.3126
Phenyltropane 11t.svg para-vinylphenyltropane
RTI-359
11t
CH-CH2 1.24 ± 0.29.5 ± 0.878 ± 4.17.762.9
Phenyltropane 11u.svg para-methylethenylphenyltropane
RTI-283 j
11u
C(=CH2)CH3 14.4 ± 0.33.13 ± 0.161330 ± 3330.292.4
Phenyltropane 11v.svg para-trans-propenylphenyltropane
RTI-296 i
11v
trans-CH=CHCH35.29 ± 0.5311.4 ± 0.281590 ± 932.1300
Phenyltropane 11x.svg para-allylphenyltropane
11x
CH2CH=CH2 32.8 ± 3.128.4 ± 2.42480 ± 2290.975.6
Phenyltropane 11y.svg para-ethynylphenyltropane
RTI-360
11y
C≡CH 1.2 ± 0.14.4 ± 0.483.2 ± 2.83.769.3
Phenyltropane 11z.svg para-propynylphenyltropane
RTI-281 i
11z
C≡CCH32.37 ± 0.215.7 ± 1.5820 ± 466.6346
Phenyltropane 11w.svg para-cis-propenylphenyltropane
RTI-304
11w
cis-CH=CHCH315 ± 1.27.1 ± 0.712,800k ± 3000.5186.6k
Phenyltropane carroll 7a.svg para-(Z)-phenylethenylphenyltropane cis-CH=CHPh 11.7 ± 1.12
Phenyltropane carroll 6b.svg para-benzylphenyltropane-CH2-Ph526 ± 657,240 ± 390
(658 ± 35)
6670 ± 377
(606 ± 277)
13.712.6
Phenyltropane carroll 6c.svg para-phenylethenylphenyltropaneCH2

-C-Ph
474 ± 1332,710 ± 800
(246 ± 73)
7,060 ± 1,760
(4,260 ± 1,060)
5.714.8
Phenyltropane carroll 5a.svg para-phenylethylphenyltropanel-(CH2)2-Ph5.14 ± 0.63234 ± 26
(21.3 ± 2.4)
10.8 ± 0.3
(6.50 ± 0.20)
45.52.1
RTI-436.svg para-(E)-phenylethenylphenyltropanel
RTI-436
trans–CH=CHPh 3.09 ± 0.75335 ± 150
(30.5 ± 13.6)
1960 ± 383
(1180 ± 231)
108.4634.3
Phenyltropane carroll 5b.svg para-phenylpropylphenyltropanel-(CH2)3-Ph351 ± 521,243 ± 381
(113 ± 35)
14,200 ± 1,800
(8,500 ± 1,100)
3.540.4
Phenyltropane carroll 8.svg para-phenylpropenylphenyltropanel-CH=CH-CH2-Ph15.8 ± 1.31781 ± 258
(71 ± 24)
1,250 ± 100
(759 ± 60)
49.479.1
Phenyltropane carroll 5c.svg para-phenylbutylphenyltropanel-(CH2)4-Ph228 ± 214,824 ± 170
(439 ± 16)
2,310 ± 293
(1,390 ± 177)
21.110.1
RTI-298 structure.svg para-phenylethynylphenyltropanel
RTI-298 [7]
–≡–Ph 3.7 ± 0.1646.8 ± 5.8
(4.3 ± 0.53)
347 ± 25
(209 ± 15)
12.693.7
Phenyltropane Carroll 4b.svg para-phenylpropynylphenyltropanel [8] –C≡C-CH2Ph1.82 ± 0.4213.1 ± 1.7
(1.19 ± 0.42)
27.4 ± 2.6
(16.5 ± 1.6)
7.115
RTI-430.svg para-phenylbutynylphenyltropanel
RTI-430
–C≡C(CH2)2Ph6.28 ± 1.252180 ± 345
(198 ± 31)
1470 ± 109
(885 ± 66)
347.1234
Phenyltropane carroll 4d.svg para-phenylpentynylphenyltropanel–C≡C-(CH2)3-Ph300 ± 371,340 ± 232
(122 ± 21)
4,450 ± 637
(2,680 ± 384)
4.4614.8
Para-trimethylsilylethynyl-phenyltropane.svg para-trimethylsilylethynylphenyltropane [3]
Para-hydroxypropynyl-phenyltropane.svg para-hydroxypropynylphenyltropane [3]
Phenyltropane carroll 4e.svg para-hydroxyhexynylphenyltropanel–C≡C-(CH2)4OH57 ± 4828 ± 29
(75 ± 2.6)
9,500 ± 812
(5,720 ± 489)
14.5166.6
Tamagnan.svg para-(thiophen-3-yl)phenyltropane
Tamagnan [4]
p-thiophene 120.0171890.00141615.7
Phenyltropane 11aa.svg para-biphenyltropane
11aa
Ph 10.3 ± 2.6f
29.4 ± 3.8ɑ
15.6 ± 0.6
95.8 ± 36
(8.7 ± 3.3)
1,480 ± 269
(892 ± 162)
6.194.8
Phenyltropane 11bb.svg 3β-2-naphthyltropane
RTI-318
11bb
3β-2-naphthyl 0.51 ± 0.03
3.32 ± 0.08f
3.53 ± 0.09ɑ
0.80 ± 0.06
(0.07 ± 0.1)
21.1 ± 1.0
(12.7 ± 0.60)
1.541.3
Phenyltropane 15.svg para-bimethoxyphenyltropane
15
OCH2OCH3h
  • ɑ[3H]DA uptake displacement Ki value.
  • b[3H]5-HT uptake displacement Ki value.
  • c[3H]NE uptake displacement Ki value.
  • d[3H]5-HT uptake to [3H]DA uptake ratio.
  • e[3H]NE uptake to [3H]DA uptake ratio.
  • fIC50 for displacement of [3H]cocaine.
  • gValues from alternate data-set differing from that used in rest of table.
  • hOriginal source (Scheme 4, page 931, 7th of article) [1] name given for compound (bottom of first ¶) is at variance with formula in scheme on same page: i.e. "methoxymethyl" versus "methoxymethoxy"
  • iProtonated as the (-)—tartrate salt (isomer)
  • jProtonated as the tartrate salt
  • kWas cited by S. Singh as 28,000nM for SERT or a DAT/SERT ratio of 1,867. However, in Singh's paper he cited J. Med. Chem. 1996, 39, 4030, Table 1 [9] which shows a ten times lower value, which is consistent with numerous RTI patents published showing the ten-× lower value.
  • lWhereas many bulky additions to the arene unit of phenyltropanes hinder and impair affinity, it has been observed that the para-substituted rigid triple bond analogs terminating in a second phenyl (off of the initial C3 position phenyl) have a high-binding affinity, putatively attesting to the existence of another binding domain that extends beyond the usual ending point where the benzene accords to the acceptor somewhere along the length of range inhabited by the DAT, corresponding to a 180° extension outward from the para area of the aryl of these type of ligands. [8]

(4′-Monosubstituted 2,3-Thiophene phenyl)-tropanes

Tamagnan (thiophene) analogues of para-phenyltropanes. [4]
Compound structureAlphanumeric code
(name)
para-substitutionN8SERTDATNETSelectivity
SERT versus DAT
Selectivity
SERT versus NET
1
(cocaine)
(—)-CocaineCH310508933200.083.2
2
(β-CIT), (Iometopane)
IodoCH30.46 ± 0.060.96 ± 0.152.80 ± 0.402.16.1
(R,S-Citalopram)1.6016,5406,19010,3383,869
Tamagnan 4a.svg 4a2-ThiopheneCH30.15 ± 0.01552 ± 12.8158 ± 123461,053
Tamagnan.svg 4b
(Tamagnan)
3-ThiopheneCH30.017 ± 0.00412.1 ± 3189 ± 8271011,118
Tamagnan 4c.svg 4c2-(5-Br)-ThiopheneCH30.38 ± 0.0086.43 ± 0.9324 ± 1917853
Tamagnan 4d.svg 4d2-(5-Cl)-ThiopheneCH30.64 ± 0.044.42 ± 1.64311 ± 256.9486
Tamagnan 4e.svg 4e2-(5-I)-ThiopheneCH34.56 ± 0.8422.1 ± 3.21,137 ± 1234.9249
Tamagnan 4f.svg 4f2-(5-NH2)-ThiopheneCH364.7 ± 3.7>10,000>30,000>155>464
Tamagnan 4g.svg 4g2-(4,5-NO2)-ThiopheneCH35,000>30,000>10,000>6.0>2.0
Tamagnan 4h.svg 4h3-(4-Br)-ThiopheneCH34.02 ± 0.34183 ± 69>10,00046>2,488
Tamagnan 5a.svg 5a2-ThiopheneH0.11 ± 0.00612.2 ± 0.975.3 ± 9.6111685
Tamagnan 5b.svg 5b3-ThiopheneH0.23 ± 0.026.4 ± 0.2739 ± 0.828170

(3′,4′-Disubstituted phenyl)-tropanes

RTI-318 structure.png
RTIthreefivethree.png
Phenyltropane 17c.svg
RTI-112.svg
Compound
(+ S. Singh's name)
X
(4′-para)
Y
(3′-meta)
2 Positionconfig8DA5-HTNE
RTI-318
11bb
β-naphthylCO2Meβ,βNMe0.50.8120
Dichloropane (RTI-111ɑ) [10]
17c
ClClCO2Meβ,βNMe0.793.1318.0
RTI-88 [recheck]
17e
NH2ICO2Meβ,βNMe1.351329c320c
RTI-97
17d
NH2BrCO2Meβ,βNMe3.91181282
RTI-112 b
17b
ClMeCO2Meβ,βNMe0.8210.536.2
RTI-96
17a
FMeCO2Meβ,βNMe2.9576520
RTI-295 EtICO2Meβ,βNMe21.32.961349
RTI-353 (EINT)EtICO2Meβ,βNH3310.69148
RTI-279 MeICO2Meβ,βNH5.981.0674.3
RTI-280 MeICO2Meβ,βNMe3.126.81484
Meltzer [11] catechol CO2Meβ,βNMe>100??
Meltzer [11] OAcOAcCO2Meβ,βNMe???
Para-meta-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes [1]
Compound Phenyltropane 16-17.svg Short Name
(S. Singh)
R2R1DA5HTNESelectivity
5-HTT/DAT
Selectivity
NET/DAT
Phenyltropane 16a.svg meta-fluorophenyltropane
16a
FH23 ± 7.8----
Phenyltropane 16b.svg meta-chlorophenyltropane
16b
ClH10.6 ± 1.8----
Phenyltropane 16c.svg meta-bromophenyltropane
16c
BrH7.93 ± 0.08ɑ----
Phenyltropane 16d.svg meta-iodophenyltropane
16d
IH26.1 ± 1.7----
Phenyltropane 16e.svg meta-tributylstannylphenyltropane
16e
SnBu3H1100 ± 170----
Methyl (1R,2S,3S,5S)-3-(3-ethynylphenyl)-8-methyl-8-azabicyclo(3.2.1)octane-2-carboxylate.svg meta-ethynylphenyltropane [3] C≡CHH-----
Phenyltropane 17a.svg meta-methyl-para-fluorophenyltropane
RTI-96
17a
CH3F2.95 ± 0.58----
RTI-112.svg meta-methyl-para-chlorophenyltropane
RTI-112 c
17b
CH3Cl0.81 ± 0.0510.5 ± 0.0536.2 ± 1.013.044.7
Phenyltropane 17c.svg meta-para-dichlorophenyltropane
RTI-111 b [10] Dichloropane
17c
ClCl0.79 ± 0.08b3.13 ± 0.36b18.0 ± 0.8
17.96 ± 0.85'b'd
4.0b22.8b
Phenyltropane 17d.svg meta-bromo-para-aminophenyltropane
RTI-97
17d
BrNH23.91 ± 0.5918128246.272.1
Phenyltropane 17e.svg meta-iodo-para-aminophenyltropane
RTI-88
17e
INH21.35 ± 0.11120 ± 41329 ± 12488.9984
Phenyltropane 17f.svg meta-iodo-para-azidophenyltropane
17f
IN34.93 ± 0.32----
3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropanes [12]
Structure Di-subst thio sulfonyl phenyltropanes.png CompoundRXnInhibition of [3H]WIN 35,428
@ DAT
IC50 (nM)
Inhibition of [3H]Paroxetine
@ 5-HTT
Ki (nM)
Inhibition of [3H]Nisoxetine
@ NET
Ki (nM)
NET/DAT
(uptake ratio)
NET/5-HTT
(uptake ratio)
CocaineDes-thio/sulfinyl/sulfonyl
H
HDesmethyl
0
89.19519902221
para-methoxyphenyltropane
Singh: 11i
Des-thio/sulfinyl/sulfonyl
OCH3
H06.5 ± 1.34.3 ± 0.51110 ± 64171258
Sulfur containing phenyltropane 7a.svg 7aCH3H09 ± 30.7 ± 0.2220 ± 1024314
Sulfur containing phenyltropane 7b.svg 7bC2H5H0232 ± 344.5 ± 0.51170 ± 3005260
Sulfur containing phenyltropane 7c.svg 7cCH(CH3)2H016 ± 223 ± 2129 ± 287
Sulfur containing phenyltropane 7d.svg 7dCF3H0200 ± 708 ± 21900 ± 30010238
Sulfur containing phenyltropane 7e.svg 7eCH3Br010.1 ± 10.6 ± 0.2121 ± 1212202
Sulfur containing phenyltropane 7f.svg 7fCH3Br176 ± 183.2 ± 0.4690 ± 809216
Sulfur containing phenyltropane 7g.svg 7gCH3H191 ± 164.3 ± 0.6515 ± 606120
Sulfur containing phenyltropane 7h.svg 7hCH3H2>10,000208 ± 45>10,000148

(2′,4′-Disubstituted phenyl)-tropanes

Ortho-para-substituted (2′,4′-disubstituted phenyltropanes)
Compound structure
Phenyltropane 2,4-subst.svg
Trivial IUPAC
(non-systematic)
Name
R2
ortho
R1
para
DA5HTNESelectivity
5-HTT/DAT
Selectivity
NET/DAT
Ortho-para-nitro-phenyltropane.svg ortho,para-dinitrophenyltropane [13] NO2NO2-----

(3′,4′,5′-Trisubstituted para-methoxyphenyl)-tropanes

Para-meta(3′)-meta(5′)-(di-meta)-substituted 2β-carbomethoxy-(3′,4′,5′-substituted phenyl)tropanes [14]
Para-methoxy/(ethoxy)-meta-substituted phenyltropanes
Structure
Phenyltropanes Carroll generic.svg
Short Name
(All compounds tested as HCl salts)
R2
3′-(meta)
R3
5′-(di-meta)
OR1
4′-(para)
DAT
IC50
[3H](compound #)12
5-HTT
Ki
[3H]Paroxetine
NET
Ki
[3H]Nisoxetine
Selectivity
NET/DAT
Ratio
Ki/IC50
Selectivity
NET/5-HTT
Ratio
Ki/Ki
Cocaine---89.19519902221
6
RTI-112
---0.82 ± 0.050.95 ± 0.0421.8 ± 0.62723
Cocaine analog Carroll 7a.svg
7a
11i
HHCH36.5 ± 1.34.3 ± 0.51110 ± 64171258
Cocaine analog Carroll 7b.svg
7bHHC2H592 ± 81.7 ± 0.41690 ± 5018994
Cocaine analog Carroll 7c.svg
7cFHCH316 ± 14.8 ± 0.5270 ± 501756
Cocaine analog Carroll 7d.svg
7dBrHCH347 ± 153.1 ± 0.1160 ± 20352
Cocaine analog Carroll 7f.svg
7fBrBrCH392 ± 222.9 ± 0.14100 ± 400ɑ451413
Cocaine analog Carroll 7e.svg
7eIHCH3170 ± 603.5 ± 0.4180 ± 20151
Cocaine analog Carroll 7g.svg
7gIICH31300 ± 2007.5 ± 0.8180 ± 204667

ɑN=2

(2′,4′,5′-Trisubstituted phenyl)-tropanes

Ortho-para(4′)-meta(5′)-trisubstituted 2β-carbomethoxy-(2′,4′,5′-substituted phenyl)tropanes [3]
StructureShort NameR1
2′-(ortho)
R2
4′-(para)
R3
5′-(meta)
DAT5-HTTNETSelectivity
NET/DAT
Ratio
Selectivity
NET/5-HTT
Ratio
Methyl (1R,2S,3S,5S)-3-(4-ethyl-2,5-diiodophenyl)-8-methyl-8-azabicyclo(3.2.1)octane-2-carboxylate.svg para-ethyl-ortho, meta-diiodophenyltropane [3] iodoethyliodo-----

2-Carbmethoxy modified (replaced/substituted)

General 2-carbmethoxy modifications

2β-substitutions of p-methoxy-phenyltropanes

Para-OCH3-(3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid ester analogues [15]
Structure
Phenyltropane generic ester.svg
Short Name
(All compounds tested as HCl salts)
CO2R (2β-substituted)
(compound 9 is 2β=R)
DAT
IC50
[3H](compound #)12
5-HTT
Ki
[3H]Paroxetine
NET
Ki
[3H]Nisoxetine
Selectivity
NET/DAT
Ratio
Ki/IC50
Selectivity
NET/5-HTT
Ratio
Ki/Ki
Cocaine analog Carroll 7a.svg
7a
11i
CH36.5 ± 1.34.3 ± 0.51110 ± 64171258
Cocaine analog Carrol 8a.svg
8a(CH3)2CH14 ± 3135 ± 352010 ± 20014415
Cocaine analog Carrol 8b.svg
8bcyclopropane6.0 ± 229 ± 31230 ± 14020542
Cocaine analog Carrol 8c.svg
8ccyclobutane13 ± 3100 ± 8>300023130
Cocaine analog Carrol 8d.svg
8dO2N...1,4-xylene...(CH2)242 ± 82.9 ± 0.2330 ± 208114
Cocaine analog Carrol 8e.svg
8eH2N...1,4-xylene...(CH2)27.0 ± 28.3 ± 0.42200 ± 300ɑ314265
Cocaine analog Carrol 8f.svg
8fCH3CONH...1,4-xylene...(CH2)26.0 ± 15.5 ± 0.51460 ± 30243265
Cocaine analog Carrol 8g.svg
8gH2N...2-bromo-1,4-dimethylbenzene...(CH2)23.3 ± 1.44.1 ± 0.61850 ± 90561451
Cocaine analog Carrol 8h.svg
8hH2N...1,3-dibromo-2,5-dimethylbenzene...(CH2)215 ± 62.0 ± 0.42710 ± 250ɑ1811360
Cocaine analog Carrol 8i.svg
8iH2N...2-iodo-1,4-dimethylbenzene...(CH2)22.5 ± 0.73.5 ± 12040 ± 300ɑ816583
Cocaine analog Carrol 8j.svg
8jH2N...1,3-diiodo-2,5-dimethylbenzene...(CH2)2102 ± 151.0 ± 0.12600 ± 200ɑ252600
Cocaine analog Carroll 9.svg
93-(4-methylphenyl)-1,2-oxazole18 ± 6860 ± 170>30001673

ɑN=2

2β-carboxy side-chained (p-chloro/iodo/methyl) phenyltropanes

Multi-substituted structures of 2β-ester-3β-phenyltropanes [1]
Compound
Phenyltropane generic subst.svg
Short Name
(S. Singh)
RXIC50 (nM)
DAT
[3H]WIN 35428
IC50 (nM)
5-HTT
[3H]paroxetine
IC50 (nM)
NET
[3H]nisoxetine
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
Phenyltropane 23a.svg 23aCH(CH3)2H85.1 ± 2.523121 ± 397632047 ± 1491272376
Phenyltropane 23b.svg 23bC6H5H76.7 ± 3.6106149 ± 725619262 ± 5931384251
Phenyltropane 24a.svg 24aCH(CH3)2Cl1.4 ± 0.13
6.04 ± 0.31ɑ
1400 ± 7
128 ± 15b
778 ± 21
250 ± 0.9c
1000
21.2d
556
41.4e
Phenyltropane 24b.svg 24bcyclopropylCl0.96 ± 0.10168 ± 1.8235 ± 8.39175245
Phenyltropane 24c.svg 24cC6H5Cl1.99 ± 0.05
5.25 ± 0.76ɑ
2340 ± 27
390 ± 34b
2960 ± 220
242 ± 30c
1176
74.3d
1.3
41.6e
Phenyltropane 24d.svg 24dC6H4-4-ICl32.6 ± 3.91227 ± 176967.6 ± 26.337.629.7
Phenyltropane 24e.svg 24eC6H4-3-CH3Cl9.37 ± 0.522153 ± 1432744 ± 140230293
Phenyltropane 24f.svg 24fC6H4-4-CH3Cl27.4 ± 1.51203 ± 421277 ± 11843.946.6
Phenyltropane 24g.svg 24gC6H4-2-CH3Cl3.91 ± 0.233772 ± 3844783 ± 3879651223
Phenyltropane 24h.svg 24hC6H4-4-ClCl55 ± 2.316914 ± 10564883 ± 28830788.8
Phenyltropane 24i.svg 24iC6H4-4-OCH3Cl71 ± 5.619689 ± 18431522 ± 9427721.4
Phenyltropane 24j.svg 24j(CH2)2C6H4-4-NO2Cl2.71 ± 0.13----
Phenyltropane 24k.svg 24k(CH)2C6H4-4-NH2Cl2.16 ± 0.25----
Phenyltropane 24l.svg 24l(CH2)2C6H3-3-I-4-NH2Cl2.51 ± 0.25----
Phenyltropane 24m.svg 24m(CH2)2C6H3-3-I-4-N3Cl14.5 ± 0.94----
Phenyltropane 24n.svg 24n(CH2)2C6H4-4-N3Cl6.17 ± 0.57----
Phenyltropane 24o.svg 24o(CH2)2C6H4-4-NCSCl5.3 ± 0.6----
Phenyltropane 24p.svg 24p(CH2)2C6H4-4-NHCOCH2BrCl1.73 ± 0.06----
Phenyltropane 25a.svg 25aCH(CH3)2I0.43 ± 0.05
2.79 ± 0.13ɑ
66.8 ± 6.53
12.5 ± 1.0b
285 ± 7.6
41.2 ± 3.0c
155
4.5d
663
14.8e
Phenyltropane 25b.svg 25bcyclopropylI0.61 ± 0.0815.5 ± 0.72102 ± 1125.4167
Phenyltropane 25c.svg 25cC6H5I1.51 ± 0.34
6.85 ± 0.93ɑ
184 ± 22
51.6 ± 6.2b
3791 ± 149
32.7 ± 4.4c
122
7.5d
2510
4.8e
Phenyltropane 26a.svg 26aCH(CH3)2CH36.45 ± 0.85
15.3 ± 2.08ɑ
6090 ± 488
917 ± 54b
1926 ± 38
73.4 ± 11.6c
944
59.9d
299
4.8e
Phenyltropane 26b.svg 26bCH(C2H5)2CH319.1 ± 14499 ± 5573444 ± 44235180
Phenyltropane 26c.svg 26ccyclopropylCH317.8 ± 0.76485 ± 212628 ± 25227.2148
Phenyltropane 26d.svg 26dcyclobutylCH33.74 ± 0.522019 ± 1334738 ± 3225401267
Phenyltropane 26e.svg 26ecyclopentylCH31.68 ± 0.141066 ± 109644 ± 28634383
Phenyltropane 26f.svg 26fC6H5CH33.27 ± 0.06
9.13 ± 0.79ɑ
24500 ± 1526
1537 ± 101b
5830 ± 370
277 ± 23c
7492
168d
1783
30.3e
Phenyltropane 26g.svg 26gC6H4-3-CH3CH38.19 ± 0.905237 ± 4532136 ± 208639261
Phenyltropane 26h.svg 26hC6H4-4-CH3CH381.2 ± 1615954 ± 6144096 ± 12119650.4
Phenyltropane 26i.svg 26iC6H4-2-CH3CH323.2 ± 0.9711040 ± 50425695 ± 13944761107
Phenyltropane 26j.svg 26jC6H4-4-ClCH3117 ± 7.942761 ± 23999519 ± 86436581.3
Phenyltropane 26k.svg 26kC6H4-4-OCH3CH395.6 ± 8.882316 ± 78523151 ± 28286133.0
  • ɑKi value for displacement of [3H]DA uptake.
  • bKi value for displacement of [3H]5-HT uptake.
  • cKi value for displacement of [3H]NE uptake.
  • d[3H]5-HT uptake to [3H]DA uptake ratio.
  • e[3H]NE uptake to [3H]DA uptake ratio.

Carboxyaryl

RTI-204 structure.png
RTIoneonethree.png
RTI-120 structure.png
CompoundX2 Positionconfig8DA5-HTNE
RTI-122 I-CO2Phβ,βNMe1.501843,791
RTI-113 Cl-CO2Phβ,βNMe1.982,3362,955
RTI-277 NO2-CO2Phβ,βNMe5.942,9105,695
RTI-120 [recheck]Me-CO2Phβ,βNMe3.2624,4715,833
RTI-116 Cl-CO2(p-C6H4I)β,βNMe331,227968
RTI-203 ClCO2(m-C6H4Me)β,βNMe9.3721532744
RTI-204 Cl-CO2(o-C6H4Me)β,βNMe3.913,7724,783
RTI-205 Me-CO2(m-C6H4Me)β,βNMe8.195,2372,137
RTI-206 Cl-CO2(p-C6H4Me)β,βNMe27.41,2031,278

2-Phenyl-3-Phenyltropanes

2-Phenyl-3-phenyltropane binding affinities and inhibition of DA & 5-HT Uptake [1]
Compound StructureShort Name
(S. Singh)
StereochemistryX
(para)
DAT
[3H]WIN 35428 IC50 (nM)
DAT
[3H]Mazindol Ki (nM)
5-HTT
[3H]Paroxetine IC50 (nM)
[3H]DA uptake Ki (nM)[3H]5-HT uptake Ki (nM)Selectivity
[3H]5-HT/[3H]DA
Cocaine(2β,3β)(H)89 ± 4.82811050 ± 894231550.4
Singh 67a.svg 67a2β,3βH12.6 ± 1.814.921000 ± 332028.9110038.1
Singh 67b.svg 67b2β,3αH-13.8-11.775364.3
Singh 67c.svg 67c2α,3αH690 ± 37-41300 ± 5300---
Singh 68.svg 682β,3αF-6.00-4.5812226.6
Singh 69a.svg 69a2β,3βCH31.96 ± 0.082.5811000 ± 832.8773.825.7
Singh 69b.svg 69b2β,3αCH3-2.87-4.1628769.0
Singh 69c.svg 69c2α,3αCH3429 ± 59-15800 ± 3740---

Carboxyalkyl

RTI-77 structure.png
RTI-121.png
RTI-150.png
CodeX2 Positionconfig8DA5-HTNE
RTI-77 ClCH2C2(3-iodo-p-anilino)β,βNMe2.512247
RTI-121 IPCITI-CO2Priβ,βNMe0.4366.8285
RTI-153 I-CO2Priβ,βNH1.063.59132
RTI-191 I-CO2Prcycβ,βNMe0.6115.5102
RTI-114 Cl-CO2Priβ,βNMe1.401,404778
RTI-278 NO2-CO2Priβ,βNMe8.142,1474,095
RTI-190 Cl-CO2Prcycβ,βNMe0.96168235
RTI-193 Me-CO2Prcycβ,βNMe1.681,066644
RTI-117 Me-CO2Priβ,βNMe6.456,0901,926
RTI-150 Me-CO2Bucycβ,βNMe3.742,0204,738
RTI-127 Me-CO2C(H)Et2β,βNMe1945003444
RTI-338 ethyl-CO2C2Phβ,βNMe11047.413366

Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.

Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.

2-Alkyl Esters & Ethers

Esters (2-Alkyl)
2β-Alkyl Ester Phenyltropanes [1]
StructureShort Name
(S. Singh)
2β=RKi (nM)
DAT
[3H]WIN 35428
IC50 (nM)
[3H]DA uptake
Selectivity
uptake/binding
Singh 59a.svg 59aCH=CHCO2CH322 ± 2123 ± 655.6
Singh 59b.svg 59bCH2CH2CO2CH323 ± 2166 ± 687.2
Singh 59c.svg 59c(CH2)2CH=CHCO2CH320 ± 2203 ± 7710.1
Singh 59d.svg 59d(CH22)4CO2CH330 ± 2130 ± 74.3
Singh 59e.svg 59eCH=CHCH2OH26 ± 3159 ± 436.1
Singh 59f.svg 59fCH2CH2CH2OH11 ± 164 ± 325.8
Singh 59g.svg 59gCH2CH2COC6H528 ± 247 ± 151.7
Ethers (2-Alkyl)

See the N-desmethyl Paroxetine homologues

2-Alkyl Ether Phenyltropanes [1]
Molecular StructureShort Name
(S. Singh)
StereochemistryDAT
[3H]WIN 35428 IC50 (nM)
5-HTT
[3H]Paroxetine IC50 (nM)
NET
[3H]Nisoxetine IC50 (nM)
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
Paroxetine623 ± 250.28 ± 0.02535 ± 150.00040.8
Singh 60a.svg R-60a2β,3β308 ± 20294 ± 185300 ± 4500.917.2
Singh 60b.svg R-60b2α,3β172 ± 8.852.9 ± 3.626600 ± 12000.3155
Singh 60c.svg R-60c2β,3α3.01 ± 0.242.2 ± 16123 ± 9.514.140.9
Singh 60d.svg S-60d2β,3β1050 ± 4588.1 ± 2.827600 ± 11000.0826.3
Singh 60e.svg S-60e2α,3β1500 ± 74447 ± 472916 ± 19500.31.9
Singh 60f.svg S-60f2β,3α298 ± 17178 ± 1312400 ± 7200.641.6

Carboxamides

U.S. patent 5,736,123

RTI-183 structure.png
RTI-229 structure.png
RTI-227 structure.png
Structure Phenyltropane 27-29.svg Code
(S. Singh #)
X2 Positionconfig8DA
[3H]WIN 35428 (IC50 nM)
NE
[3H]nisoxetine
5-HT
[3H]paroxetine (IC50 nM)
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
Phenyltropane 27b.svg RTI-106
27b
ClCON(H)Meβ,βNMe12.4 ± 1.171584 ± 621313 ± 46106128
Phenyltropane 27a.svg RTI-118
27a
ClCONH2β,βNMe11.5 ± 1.64270 ± 3591621 ± 110141371
Phenyltropane 29d.svg RTI-222
29d
Memorpholinylβ,βNMe11.7 ± 0.8723601 ± 1156>100K>85472017
Phenyltropane 27e.svg RTI-129
27e
ClCONMe2β,βNMe1.38 ± 0.1942 ± 481079 ± 102792683
Phenyltropane 27d.svg RTI-146
27d
ClCONHCH2OHβ,βNMe2.05 ± 0.23144 ± 397.8 ± 1047.770.2
Phenyltropane 27i.svg RTI-147
27i
ClCON(CH2)4β,βNMe1.38 ± 0.033,950 ± 7212400 ± 120789852862
RTI-156.svg RTI-156 ClCON(CH2)5β,βNMe6.6158323468
RTI-170.svg RTI-170 ClCON(H)CH2C≡CHβ,βNMe16.518394827
RTI-172.svg RTI-172 ClCON(H)NH2β,βNMe44.139143815
RTI-174.svg RTI-174 ClCONHCOMeβ,βNMe158>43K>125K
RTI-182.svg RTI-182 ClCONHCH2COPhβ,βNMe7.791722827
Phenyltropane 27g.svg RTI-183
27 g
ClCON(OMe)Meβ,βNMe0.85 ± 0.06549 ± 18.5724 ± 94852646
Phenyltropane 29c.svg RTI-186
29c
MeCON(OMe)Meβ,βNMe2.55 ± 0.43422 ± 263402 ± 3531334165
Phenyltropane 27h.svg RTI-198
27h
ClCON(CH2)3β,βNMe6.57 ± 0.67990 ± 4.8814 ± 57124151
Phenyltropane 27c.svg RTI-196
27c
ClCONHOMeβ,βNMe10.7 ± 1.259907 ± 63243700 ± 19604084926
RTI-201.svg RTI-201 ClCONHNHCOPhβ,βNMe91.8>20K>48K
Phenyltropane 27j.svg RTI-208
27j
ClCONO(CH2)3β,βNMe1.47 ± 0.131083 ± 762470 ± 561680737
Phenyltropane 27l.svg RTI-214
27l
ClCON(-CH2CH2-)2Oβ,βNMe2.90 ± 0.38545 ± 20688769 ± 1855306102946
Phenyltropane 27f.svg RTI-215
27f
ClCONEt2β,βNMe5.48 ± 0.195532 ± 2999433 ± 77017211009
RTI-217.svg RTI-217 ClCONH(m-C6H4OH)β,βNMe4.78>30K>16K
RTI-218.svg RTI-218 ClCON(Me)OMeβ,βNMe1.195201911
Phenyltropane 27m.svg RTI-226
27 m
ClCONMePhβ,βNMe45.5 ± 32202 ± 49523610 ± 212851948.4
RTI-227.svg RTI-227 ICONO(CH2)3β,βNMe0.75446230
Phenyltropane 28a.svg RTI-229 [16]
28a
ICON(CH2)4β,βNMe0.37 ± 0.04991 ± 211728 ± 3946702678
Phenyltropane 27k.svg 27k6.95 ± 1.211752 ± 2023470 ± 226499252
Phenyltropane 28b.svg 28b1.08 ± 0.15103 ± 6.273.9 ± 8.168.495.4
Phenyltropane 28c.svg 28c0.75 ± 0.02357 ± 42130 ± 15.8173476
Phenyltropane 29a.svg 29a41.8 ± 2.454398 ± 2716371 ± 374152105
Phenyltropane 29b.svg 29b24.7 ± 1.936222 ± 72933928 ± 21921374252

✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.

2β-Carboxamide-3β-Phenyltropanes [1]
CompoundShort Name
(S. Singh)
RXIC50 (nM)
DAT
[3H]WIN 35428
IC50 (nM)
5-HTT
[3H]Paroxetine
IC50 (nM)
NET
[3H]Nisoxetine
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
Phenyltropane 27-29.svg
29aNH2CH341.8 ± 2.456371 ± 3744398 ± 271152105
29bN(CH2CH3)2CH324.7 ± 1.9333928 ± 21926222 ± 7291374252
29c
RTI-186
N(OCH3)CH3CH32.55 ± 0.433402 ± 353422 ± 261334165
29d
RTI-222
4-morpholineCH311.7 ± 0.87>10000023601 ± 1156>85472017

Carboxamide linked phenyltropanes dimers

Phenyltropane para chloro dimer.svg Phenyltropane para methyl dimer.svg PhenyltropaneDimerC2Benzenelink.svg PhenyltropaneDimerC2amide.svg PhenyltropaneDimer.svg
Dimers of phenyltropanes, connected in their dual form using the C2 locant as altered toward a carboxamide structural configuring (in contrast and away from the usual inherent ecgonine carbmethoxy), as per Frank Ivy Carroll's patent inclusive of such chemical compounds, possibly so patented due to being actively delayed pro-drugs in vivo. [3]

Heterocycles

These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize [17] to the energetically more favorable trans configuration. This can happen to cocaine also.

Atomic positions A--C
(compound model 34) HeterocyclicMEPCmpndModel34.png
Atomic positions A—C
(compound model 34)

Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.

To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔVmin(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔVmin(A): wherein the values for the latter for 32c = 0, 32g = -4, 32h = -50 & 32i = -63 kcal/mol.

In contrast to this trend, it is understood that an increasingly negative ΔVmin is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand. [lower-alpha 7]

3-Substituted-isoxazol-5-yl

3-R-isoxazol-5-yl.svg

N-methylphenyltropanes with 1R β,β stereochemistry.
Code
(S.S. #)
XRDANE5HT
RTI-165 Cl3-methylisoxazol-5-yl0.59181572
RTI-171 Me3-methylisoxazol-5-yl0.932543818
RTI-180 I3-methylisoxazol-5-yl0.7367.936.4
RTI-177 β-CPPIT
32g
Cl3-phenylisoxazol-5-yl1.28 ± 0.18504 ± 292420 ± 136
RTI-176 Me3-phenylisoxazol-5-yl1.583985110
RTI-181 I3-phenylisoxazol-5-yl2.57868100
RTI-184 Hmethyl43.36208
RTI-185 HPh285>12K
RTI-334 Cl3-ethylisoxazol-5-yl0.501203086
RTI-335 Clisopropyl1.199542318
RTI-336 Cl3-(4-methylphenyl)isoxazol-5-yl4.0917145741
RTI-337 Cl3-t-butyl-isoxazol-5-yl7.31632137K
RTI-345 Clp-chlorophenyl6.425290>76K
RTI-346 Clp-anisyl1.577625880
RTI-347 Clp-fluorophenyl1.869187257
RTI-354 Me3-ethylisoxazol-5-yl1.622996400
RTI-366 MeR = isopropyl4.52523 (1550)42,900 (3900)
RTI-371 Mep-chlorophenyl8.74>100K (60,200)>100K (9090)
RTI-386 Mep-anisyl3.93756 (450)4027 (380)
RTI-387 Mep-fluorophenyl6.45917 (546)>100K (9400)

3-Substituted-1,2,4-oxadiazole

RTI-130 structure.png
RTI-126.png
Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.
StructureCode
(Singh's #)
XRDAT (IC50nM)
displacement of [H3]WIN 35428
NET (IC50nM)
[H3]nisoxetine
5-HTT (IC50nM)
[H3]paroxetine
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
RTI-87.svg ααRTI-87 H3-methyl-1,2,4-oxadiazole20436K30K
RTI-119.svg βαRTI-119 H3-methyl-1,2,4-oxadiazole1677K41K
RTI-124.svg αβRTI-124 H3-methyl-1,2,4-oxadiazole102871K33K
Phenyltropane Singh 32a.svg RTI-125
(32a)
Cl3-methyl-1,2,4-oxadiazole4.05 ± 0.57363 ± 362584 ± 80063789.6
Phenyltropane Singh 31.svg ββRTI-126 [18]
(31)
H3-methyl-1,2,4-oxadiazole100 ± 67876 ± 5513824 ± 42038.3788
Phenyltropane Singh 32c.svg RTI-130
(32c)
Cl3-phenyl-1,2,4-oxadiazole1.62 ± 0.02245 ± 13195 ± 5120151
Phenyltropane Singh 32d.svg RTI-141
(32d)
Cl3-(p-anisyl)-1,2,4-oxadiazole1.81 ± 0.19835 ± 8337 ± 40186461
Phenyltropane Singh 32e.svg RTI-143
(32e)
Cl3-(p-chlorophenyl)-1,2,4-oxadiazole4.06 ± 0.2240270 ± 180
(4069)
404 ± 5699.59919
Phenyltropane Singh 32f.svg RTI-144
(32f)
Cl3-(p-bromophenyl)-1,2,4-oxadiazole3.44 ± 0.361825 ± 170106 ± 1030.8532
Phenyltropane Singh 33.svg βRTI-151
(33)
Me3-phenyl-1,2,4-oxadiazole2.33 ± 0.2660 ± 21074 ± 13045925.7
RTI-152.svg αRTI-152 Me3-phenyl-1,2,4-oxadiazole4941995
Phenyltropane Singh 32b.svg RTI-154
(32b)
Cl3-isopropyl-1,2,4-oxadiazole6.00 ± 0.55135 ± 133460 ± 25057722.5
RTI-155.svg RTI-155 Cl3-cyclopropyl-1,2,4-oxadiazole3.411774362
RTI-470 structure.png
RTI-4229-470 structure. Highly excited 94 pM DAT signal. [19]

above: 2D skeletal depiction.

below: 3D tube model.
RTI-4229-470 with tube model.png
Heterocyclic tropanes.png
RTI-371 structure.png
N-methylphenyltropanes with 1R β,β stereochemistry.
StructureCodeX2 GroupDAT (IC50nM)
displacement of [H3]WIN 35428
NET (IC50nM)

displacement of [H3]nisoxetine
5-HTT (IC50nM)

displacement of [H3]paroxetine
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
RTI-157.svg RTI-157 Metetrazole1557>37K>43K
RTI-163.svg RTI-163 Cltetrazole9115456
RTI-178.svg RTI-178 Me5-phenyl-oxazol-2-yl35.46771699
RTI-188.svg RTI-188 Cl5-phenyl-1,3,4-oxadiazol-2-yl12.69303304
Phenyltropane Singh 32i.svg RTI-189
(32i)
Cl5-phenyl-oxazol-2-yl19.7 ± 1.98496 ± 421120 ± 10756.825.5
RTI-194.svg RTI-194 Me5-methyl-1,3,4-oxadiazol-2-yl4.452534885
RTI-195.svg RTI-195 Me5-phenyl-1,3,4-oxadiazol-2-yl47.51310>22,000
RTI-199.svg RTI-199 Me5-phenyl-1,3,4-thiadiazol-2-yl35.9>24,000>51,000
RTI-200.svg RTI-200 Cl5-phenyl-1,3,4-thiadiazol-2-yl15.34142>18,000
RTI-202.svg RTI-202 Clbenzothiazol-2-yl1.374031119
RTI-219.svg RTI-219 Cl5-phenylthiazol-2-yl5.71851610,342
RTI-262 Cl188.2 ± 5.01595.25 ± 57385207 ± 48831628
RTI-370.svg RTI-370 Me3-(p-cresyl)isoxazol-5-yl8.746980>100K
RTI-371.svg RTI-371 Cl3-(p-chlorophenyl)isoxazol-5-yl13>100K>100K
RTI-436-2.svg RTI-436 Me-CH=CHPh [20] 3.091960 (1181)335 (31)
RTI-470.svg RTI-470 Clo-Cl-benzothiazol-2-yl0.0941590 (994)1080 (98)
RTI-451.svg RTI-451 Mebenzothiazol-2-yl1.53476 (287)7120 (647)
Phenyltropane Singh 32g.svg 32g1.28 ± 0.18504 ± 292420 ± 1361891394
Phenyltropane Singh 32h.svg 32h12.6 ± 10.3929 ± 88330 ± 19626273.7
Above is taken from: RTI, Kuhar, et al. U.S. patent 5,935,953 (1999). Heterocyclic phenyltropane syntheses p2.png
Above is taken from: RTI, Kuhar, et al. U.S. patent 5,935,953 (1999).

N.B There are some alternative ways of making the tetrazole ring however; C.f. the sartan drugs synthesis schemes. Bu3SnN3 is a milder choice of reagent than hydrogen azide (c.f. Irbesartan).

Acyl (C2-propanoyl)

WF-23.svg
WF-31.svg
WF-11.svg
WF-33.svg
Indolyl
cf. the Tamagnan series of phenyltropanes for examples with a methylene unit spacer breaking up the indole. 3ss-(5-Indolyl)-8-azabicyclo(3.2.1)octanes.png
Indolyl
cf. the Tamagnan series of phenyltropanes for examples with a methylene unit spacer breaking up the indole.
#
(#)
XY2 Positionconfig8DA5-HTNE
WF-23
(39n)
β-naphthylC(O)Etβ,βNMe0.1150.394No data
WF-31 PIT-PriHC.O.Etβ,βNMe61554.5No data
WF-11 PTT
(39e)
MeH-C.O.Etβ,βNMe8.2131No data
WF-25
(39a)
HH-C.O.Etβ,βNMe48.31005No data
WF-33 6-MeoBNC(O)Etα,βNMe0.132.24No data
Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine i.e. tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration)
2β-acyl-3β-phenyltropane structures [lower-alpha 8]
StructureS. Singh's
alphanumeric
assignation
(name)
R1R2DAT

[125I]RTI-55 IC50 (nM)

5-HTT

[3H]Paroxetine Ki (nM)

Selectivity

5-HTT/DAT

cocaine173 ± 19
Troparil
11a
(WIN 35065-2)
98.8 ± 12.2
Singh 39a.svg WF-25
39a
C2H5C6H548.3 ± 2.81005 ± 11220.8
Singh 39b.svg 39bCH3C6H5114 ± 221364 ± 61612.0
Singh 39c.svg 39cC2H5C6H4-4-F15.3 ± 2.8630 ± 6741.2
Singh 39d.svg 39dCH3C6H4-4-F70.8 ± 13857 ± 18712.1
Singh 39e.svg WF-11
39e
C2H5C6H4-4-CH38.2 ± 1.6131 ± 116.0
(+)-39eC2H5C6H4-4-CH34.21 ± 0.0574 ± 1217.6
(-)-39eC2H5C6H4-4-CH31337 ± 122>10000
Singh 39f.svg 39fCH3C6H4-4-CH39.8 ± 0.5122 ± 2212.4
Singh 39g.svg 39gCH3C6H4-4-C2H5152 ± 2478.2 ± 220.5
Singh 39h.svg 39hC2H5C6H4-4-CH(CH3)2436 ± 4135.8 ± 4.40.08
Singh 39i.svg 39iC2H5C6H4-4-C(CH3)32120 ± 6301771 ± 4740.8
Singh 39j.svg 39jC2H5C6H4-4-C6H52.29 ± 1.084.31 ± 0.011.9
Singh 39k.svg 39kC2H5C6H4-2-CH31287 ± 322710000>7.8
Singh 39l.svg 39lC2H51-naphthyl5.43 ± 1.2720.9 ± 2.93.8
Singh 39m.svg 39mCH31-naphthyl10.1 ± 2.225.6 ± 5.12.5
Singh 39n.svg WF-23
39n
C2H52-naphthyl0.115 ± 0.0210.394 ± 0.0743.5
Singh 39o.svg 39oCH32-naphthyl0.28 ± 0.111.06 ± 0.363.8
Singh 39p.svg 39pC2H5C6H4-4-CH(C2H5)2270 ± 38540 ± 512.0
Singh 39q.svg 39qC2H5C6H4-4-C6H11320 ± 5597 ± 120.30
Singh 39r.svg 39rC2H5C6H4-4-CH=CH20.90 ± 0.343.2 ± 1.33.5
Singh 39s.svg 39sC2H5C6H4-4-C(=CH2)CH37.2 ± 2.10.82 ± 0.380.1

2β-Acyl-3β-naphthyl substituted

2β-Acyl-3β-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes [22]
StructureShort Assignation
(Numeric code, Davies UB)
S. Singh
RDAT
[125H]RTI-55ɑ
IC50 nM
SERT
[3H]paroxetineb
Ki nM
NET
[3H]nisoxetinec
Ki nM
potency ratio
SERT/DAT
potency ratio
SERT/NET
WF-11.svg WF-11
(6)
4′-Me8.2 ± 1.6131 ± 1065 ± 9.20.060.5
WF-31.svg WF-31
(7)
4′-iPr436 ± 4136 ± 4>10,00012>250
WF-23.svg WF-23
(8)
2-naphthalene0.12 ± 0.020.39 ± 0.072.9 ± 0.50.37
Davies 9a.svg 2β-acyl-3β-1-naphthalene
(9a)
4′-H5.3 ± 1.321 ± 2.949 ± 100.318
Davies 9b.svg (9b)4′-Me25.1 ± 0.58.99 ± 1.70163 ± 36318
Davies 9c.svg (9c)4′-Et75.1 ± 11.9175 ± 254769 ± 6880.727
Davies 9d.svg (9d)4′-iPr225 ± 36136 ± 64>10,0002>73.5
Davies 10a.svg (10a)6′-Et0.15 ± 0.040.38 ± 0.1927.7 ± 9.60.474
Davies 10b.svg (10b)6′-iPr0.39 ± 0.041.97 ± 0.33no data0.2
Davies 10c.svg (10ce)6′- OMe0.13 ± 0.042.24 ± 0.34no data0.05
Davies 10d.svg (10d)5′-Et, 6′-OMe30.8 ± 6.67.55 ± 1.573362 ± 1484.1445
Davies 10e.svg (10e)5′-C(Me)=CH2, 6′-OMe45.0 ± 3.788.0 ± 13.32334 ± 3780.526.5
Davies 10f.svg (10f)6′-I0.35 ± 0.070.37 ± 0.02no data1.0
Davies 10g.svg (10g)7′-I0.45 ± 0.050.47 ± 0.02no data0.5d
Davies 10h.svg (10h)5′-NO2, 6′-OMe148 ± 5015 ± 1.6no data10
Davies 10i.svg (10i)5′-I, 6′-OMe1.31 ± 0.332.27 ± 0.31781 ± 1810.6344
Davies 10j.svg (10j)5′-COMe, 6′-OMe12.6 ± 3.815.8 ± 1.65498 ± 240.832
Davies 11a.svg (11a)2β-COCH3, 1-naphthyl10 ± 2.226 ± 5.1165 ± 400.46.3
Davies 11b.svg (11b)2α-COCH3, 1-naphthyl97 ± 21217 ± 55no data0.45
Davies 11c.svg (11c)2α-COCH2CH3, 2-naphthyl2.51 ± 0.8216.4 ± 2.068.0 ± 10.80.154.1
Davies 11d.svg (11d)2β-COCH3, 2-naphthyl1.27 ± 0.151.06 ± 0.364.9 ± 1.21.24.6
Davies 11e.svg (11e)2β-COCH(CH3)2, 2-naphthyl0.25 ± 0.082.08 ± 0.8037.6 ± 10.50.1218.1
Davies 11f.svg (11f)
79a
2β-COCH2CH3, 2-naphthyl, N8-demethyl0.03 ± 0.010.23 ± 0.072.05 ± 0.90.138.9
  • ɑ nonspecific binding was determined in the presence of 1.0 μM WF-23
    (source equates WF-23 as analogue 3a, but table gives # as analogue 8)
  • b nonspecific binding was determined in the presence of 10.0 μM fluoxetine
  • c nonspecific binding was determined in the presence of 1.0 μM desipramine
  • d ratio shown as halved; a possible copy-error due to closeness to 1:1 of other indicated values
  • e sources differ on whether C2 position acyl is alpha or beta configured

Ester reduction

Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.

RTI-123 structure.png
CodeX2 Positionconfig8DA5-HTNE
RTI-100 F-CH2OHβ,βNMe474741no data
RTI-101 I-CH2OHβ,βNMe2.226no data
RTI-99 Br-CH2OHβ,βNMe1.4951no data
RTI-93 Cl-CH2OHβ,βNMe1.5320443.8
RTI-105 Cl-CH2OAcβ,βNMe1.60143127
RTI-123 Cl-CH2OBzβ,βNMe1.783.53393
RTI-145 Cl-CH2OCO2Meβ,βNMe9.602.931.48

2-Alkane/Alkene

2-Alkane/Alkene-3-Phenyltropanes
StructureSingh's #RXDAT
mazindol displacement
DA uptake5-HT UptakeSelectivity
DA uptake/DAT binding
WIN 35,065-2.svg
11a
WIN 35062-2
89.453.71860.6
Chlorophenyltropane.png
11c0.83 ± 00.728.5 ± 0.934.3
RTI-32 structure.png
11f5.766.9223.21.2
Cocaine analog 41a.svg
41a(CH2)2CH3H12.26.8986.80.6
Cocaine analog 41b.svg
41b(CH2)3C6H5H16 ± 2a43 ± 13b2.7
Cocaine analog 42.svg
42(CH2)2CH3F5.281.9921.70.4
Cocaine analog 43a.svg
43aCH=CH2Cl0.59 ± 0.152.47 ± 0.54.2
Cocaine analog 43b.svg
43bE-CH=CHClCl0.42 ± 0.041.13 ± 0.272.7
Cocaine analog 43c.svg
43cZ-CH=CHClCl0.22 ± 0.020.88 ± 0.054.0
Cocaine analog 43d.svg
43dE-CH=CHC6H5Cl0.31 ± 0.040.66 ± 0.012.1
Cocaine analog 43e.svg
43eZ-CH=CHC6H5Cl0.14 ± 0.070.31 ± 0.092.2
Cocaine analog 43f.svg
43fCH2CH3Cl2.17 ± 0.202.35 ± 0.521.1
Cocaine analog 43g.svg
43 g(CH2)2CH3Cl0.94 ± 0.081.08 ± 0.051.1
Cocaine analog 43h.svg
43h(CH2)3CH3Cl1.21 ± 0.180.84 ± 0.050.7
Cocaine analog 43i.svg
43i(CH2)5CH3Cl156 ± 15271 ± 31.7
Cocaine analog 43j.svg
43j(CH2)2C6H5Cl1.43 ± 0.031.54 ± 0.081.0
Cocaine analog 44a.svg
44a(CH2)2CH3CH31.571.1010.30.7
Cocaine analog 44b.svg
44b(CH2)3CH3CH31.821.3115.10.7
Cocaine analog 45.svg
45(CH2)2CH3H74.930.23890.4
Cocaine analog 46.svg
46(CH2)2CH3F21.112.199.60.6
Cocaine analog 47a.svg
47a(CH2)2CH3CH38.9111.850.11.3
Cocaine analog 47b.svg
47b(CH2)3CH3CH311.410.151.00.9

aKi value for displacement of WIN 35428.
bIC50 value.

Compound 48
Compound 48-H.svg
para-hydro
Compound 48-Cl.svg
para-chloro

Irreversible covalent (cf. ionic) C2 ligands

RTI-76 structure.png
Irreversible (phenylisothiocyanate) binding ligand (Murthy, V.; Martin, T. J.; Kim, S.; Davies, H. M. L.; Childers, S. R. (2008). "In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain". Journal of Pharmacology and Experimental Therapeutics. 326 (2): 587–595. doi:10.1124/jpet.108.138842. PMID   18492949. S2CID   5996473.) [23] RTI-76: [24] 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.

C2 Acyl, N8 phenylisothiocyanate

HD-205.svg
HD-205 (Murthy et al., 2007) [25]

Note the contrast to the phenylisothiocyanate covalent binding site locations as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.

Benztropine based (C2-position hetero-substituted) phenyltropanes

Benztropine phenyltropane.png BenztropinePT.png

2-(Diarylmethoxymethyl)-3β-aryltropanes & 2β-[3-(Diarylmethoxy)propyl]-3β-aryltropanes. [26] [27]
StructureCompoundRXY[3H]WIN 35,428
@ DAT
Ki (nM)
[3H]Citalopram
@ SERT
Ki (nM)
[3H]Nisoxetine
@ NET
Ki (nM)
[3H]Pirenzepine
@ M1
Ki (nM)
Benztropine phenyltropane 9.svg
9aCH3HH34 ± 2121 ± 19684 ± 10010,600 ± 1,100
9bFHH49 ± 12
9cClHH52 ± 2.1147 ± 81,190 ± 7211,000 ± 1,290
9dCH3ClH80 ± 9443 ± 604,400 ± 23831,600 ± 4,300
9eFClH112 ± 11
9fClClH76 ± 7462 ± 362,056 ± 23639,900 ± 5,050
9gCH3FF62 ± 7233 ± 241,830 ± 17715,500 ± 1,400
9hFFF63 ± 13
9iClFF99 ± 18245 ± 162,890 ± 22216,300 ± 1,300
Benztropine phenyltropane 10.svg
10aCH3HH455 ± 36530 ± 722,609 ± 19512,600 ± 1,790
10cClHH478 ± 72408 ± 163,998 ± 25611,500 ± 1,720
10dCH3ClH937 ± 841,001 ± 10922,500 ± 2,82118,200 ± 2,600
10fClClH553 ± 1061,293 ± 405,600 ± 1839,600 ± 600
10gCH3FF690 ± 76786 ± 6716,000 ± 6379,700 ± 900
10iClFF250 ± 40724 ± 10052,300 ± 13,6009,930 ± 1,090
Benztropine phenyltropane 12.svg
12aHHH139 ± 1561 ± 9207 ± 307,970 ± 631
12bHClH261 ± 1945 ± 324,600 ± 2,930
12cHFF60 ± 7

F&B series (Biotin side-chains etc.)

One patent claims a series of compounds with biotin-related sidechains are pesticides. [18]

StructureCodepara-XC2-Tropane PositionconfigDANE5-HT
Phenyltropane F1 (2-H).svg HF1β,β
Phenyltropane F1 (2-Me).svg RTI-224 MeF1cβ,β4.49155.6
Phenyltropane F2.svg RTI-233 MeF2β,β4.3851673.6
Phenyltropane F3 (N8).svg RTI-235 MeF3dβ,β1.7540272.4
Phenyltropane F3 (nortropane).svg F3β,β
Phenyltropane B1.svg RTI-236 MeB1dβ,β1.6386.8138
Phenyltropane B2.svg RTI-237 MeB2dβ,β7.27258363
Phenyltropane B3.svg RTI-244 MeB3dβ,β15.6180933.7
Phenyltropane F4.svg RTI-245 ClF4cβ,β77.3
RTI-246 MeF4cβ,β50.33000
Phenyltropane F5.svg F5β,β
Phenyltropane F6.svg RTI-248 ClF6cβ,β9.7346746.96
Phenyltropane F1 (3-Ar-4-Cl).svg RTI-249 ClF1cβ,β8.32502381.6
RTI-266 MeF2β,β4.80836842
RTI-267 MeF7 wrongβ,β2.52324455
Phenyltropane F7.svg RTI-268 MeF7 rightβ,β3.891014382
Phenyltropane F8.svg RTI-269 MeF8β,β5.55788986

F series.png B series.png

Miscellany (i.e. Misc./Miscellaneous) C2-substituents

Phenyltropane FMOC-hydrazide.svg
Phenyltropane pyrene.svg
Phenyltropane dimethylaminonaphthalene.svg
Phenyltropane pyrene hydroxamide.svg
StructureCodeX2 Positionconfig8DA5-HTNE
RTI-102.svg RTI-102 ICO2Hβ,βNMe474192843,400
RTI-103.svg RTI-103 BrCO2Hβ,βNMe278307017,400
RTI-104.svg RTI-104 FCO2Hβ,βNMe2744>100K>100K
RTI-108.svg RTI-108 Cl-CH2Clβ,βNMe2.6498129.8
RTI-241.svg RTI-241 Me-CH2CO2Meβ,βNMe1.02619124
RTI-139.svg RTI-139 Cl-CH3β,βNMe1.678557
RTI-161.svg RTI-161 Cl-C≡Nβ,βNMe13.118872516
RTI-230.svg RTI-230 ClH3C–C=CH2β,βNMe1.2857141
RTI-240.svg RTI-240 Cl-CHMe2β,βNMe1.3838.484.5
RTI-145.svg RTI-145 Cl-CH2OCO2Meβ,βNMe9.602,9321,478
RTI-158.svg RTI-158 Me-C≡Nβ,βNMe5750951624
RTI-131.svg RTI-131 Me-CH2NH2β,βNMe10.5855120
RTI-164.svg RTI-164 Me-CH2NHMeβ,βNMe13.62246280
RTI-132.svg RTI-132 Me-CH2NMe2β,βNMe3.48206137
RTI-239.svg RTI-239 Me-CHMe2β,βNMe0.6111435.6
RTI-338.svg RTI-338 Et-CO2CH2Phβ,βNMe11047.413366
RTI-348.svg RTI-348 H-Phβ,βNMe28.2>34,0002670

C2-truncated/descarboxyl (non-ecgonine w/o 2-position-replacement tropanes)

Aryl-Tropenes

WO 2004113297,Peters, Dan; Olsen, Gunnar M.& Nielsen, Elsebet Oestergaardet al.,"Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors",published 2004-12-29, assigned to NeuroSearch AS  

Test compoundDA-uptake IC50(μM)NA-uptake IC50(μM)5-HT-uptake IC50(μM)
(+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene0.260.0280.010
(+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene0.0580.0130.00034
(–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene0.0340.0180.00023
US 0 WO9713770.svg
US 0  
8-AZABICYCLO[3.2.1]OCT-2-ENE DERIVATIVES
Test CompoundDA uptake IC50(μM)NE uptake IC50(μM)5-HT uptake IC50(μM)
(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene0.0790.0260.0047

U.S. patent 2,001,047,028

Test CompoundDA uptake IC50(μM)NE uptake IC50(μM)5-HT uptake IC50(μM)
(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene184.90.047
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene1.50.50.016
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene22.008.000.0036

Enantioselective nonstandard configurations (non-2β-,3β-)

β,α Stereochemistry

RTI-319 structure.png
RTI-274 Structure.png
Structure Phenyltropanes 20a-e.svg Compound
(RTI #)

(S. Singh's #)
X2 Groupconfig8DAT IC50 (nM)
[3H]WIN 35428
5-HTT IC50 (nM)
[3H]paroxetine
NET IC50 (nM)
[3H]nisoxetine
selectivity
5-HTT/DAT
selectivity
NET/DAT
Phenyltropane 20a.svg RTI-140
20a
HCO2Meβ,αNMe101 ± 165,701 ± 7212,076 ± 28556.420.6
RTI-352.svg RTI-352 ɑ
20d
ICO2Meβ,αNMe2.86 ± 0.1664.9 ± 1.9752.4 ± 4.922.818.4
RTI-549.svg RTI-549 BrCO2Meβ,αNMe
RTI-319.svg RTI-319 b3α-2-naphthylCO2Meβ,αNMe1.1 ± 0.0911.4 ± 1.370.2 ± 6.28
Phenyltropane 20b.svg RTI-286 c
20b
FCO2Meβ,αNMe21 ± 0.575062 ± 4851231 ± 9124158.6
RTI-274.svg RTI-274 dFCH2O(3′,4′-MD-phenyl)β,αNH3.965.6214.4
RTI-287.svg RTI-287 EtCO2Meβ,αNMe327168717,819
Phenyltropane 20c.svg 20cClCO2Meβ,αNMe2.4 ± 0.2998 ± 12060.1 ± 2.441625.0
Phenyltropane 20e.svg 20eMeCO2Meβ,αNMe10.2 ± 0.084250 ± 422275 ± 2441727.0
RTI-319 alt.svg BnCO2Meβ,αNMe

Boat tropane synth.png

α,β Stereochemistry

CA 2112084  

Brasofensine.svg
CompoundDA (μM)M.E.D. (mg/kg)Dose (mg/kg)ActivityActivity
(2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane0.39<15000
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane0.112500
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane0.0160.2550++++
Tesofensine chemical structure.png
NStwothreefivenine.png

di-chloro; para- & meta- in tandem (α,β configured phenyltropanes)

U.S. patent 2,001,047,028

CompoundX2 Groupconfig8DA5-HTNE
Brasofensine Cl2methyl aldoximeα,βNMe
Tesofensine Cl2ethoxymethylα,βNMe65111.7
NS-2359 (GSK-372,475)Cl2Methoxymethylα,βNH

fumaric acid salts (of α,β configured phenyltropanes)

WO 2004072075,Peters, Dan; Nielsen, Elsebet Oestergaard& Olsen, Gunnar M.et al.,"Novel 8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors",published 2004-08-26, assigned to NeuroSearch AS  

Test CompoundDA uptake IC50(μM)NE uptake IC50(μM)5-HT uptake IC50(μM)
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0620.0350.00072
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0620.150.0063
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.100.0480.0062
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0880.0510.013

Arene equivalent alterations

η6-3β-(transition metal complexed phenyl)tropanes

x-substitution image of both the chromium & ruthenium benzene pi-symmetry facilitating PTs.

21b can be prepared from ferrocenes and perrhenate by a double ligand transfer (DLT) reaction. Cocaine analog 21ab alternate.png
×–substitution image of both the chromium & ruthenium benzene pi-symmetry facilitating PTs.

21b can be prepared from ferrocenes and perrhenate by a double ligand transfer (DLT) reaction.

Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η 6-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule. [1] (cf. the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. Bloom and Wheeler. [29] ).

21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity Ki values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.

Tricarbonyl-3b-chromium containing phenyltropane, having roughly twice the strength Ki affinity as parent compound at same mean affect. Cocaine analog 21a alternate.png
Tricarbonyl-3β-chromium containing phenyltropane, having roughly twice the strength Ki affinity as parent compound at same mean affect.

The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e.θ) is θ=131° for Cr(CO)3 whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand. [1]

Diagram indicating the triflate, in bracket, superimposed as a direct connection between the e benzene containing its transition metal fixed upon the e -penta-methyl (five-methyls) cyclopenta-dienyl (five sided ring) alongside the benzene in three dimension. Cocaine analog 21b alternate.png
Diagram indicating the triflate, in bracket, superimposed as a direct connection between the η benzene containing its transition metal fixed upon the η -penta-methyl (five-methyls) cyclopenta-dienyl (five sided ring) alongside the benzene in three dimension.
Displacement of Receptor-Bound [3H]WIN 35428 and Inhibition of [3H]DA Uptake by Transition Metal Complexes of 3β-Phenyltropanes [1]
StructureCompound #
(S. Singh)
Systematic name
Ki (nM)ɑIC50 (nM)selectivity
binding/uptake
Cocaine analog 21a.svg
21ac17 ± 15b
224 ± 83
41824.6
Cocaine analog 21b.svg
21bd2280 ± 18338901.7
Cocaine 32 ± 5
388 ±221
40512.6
Troparil (11a)33 ± 17
314 ± 222
37311.3

3-(2-thiophene) and 3-(2-furan)

U.S. patent 7,247,643 Cocaine analogs - thiophenes and furans.svg
U.S. patent 7,247,643
CodeCompoundDA (μM)NE (μM)5-HT (μM)
1(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt0.300.00190.00052
2(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.360.00360.00042
3(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.310.000900.00036
4(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.920.00300.00053
5(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt0.0740.00180.00074
6(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt0.190.00160.00054

Thiophenyltropanes

Thiophenyltropanes.png

Diaryl

Fluoxetine homologue, also: Hanna et al. (2007) Hanna et al.png
Fluoxetine homologue, also: Hanna et al. (2007)
cf. the paroxetine homologue PTs
ZIENT: ZIENT.png
ZIENT:

6/7-tropane position substituted

2β-carbomethoxy 6/7 substituted

6/7-Substituted 2-carbomethoxy-phenyltropanes [1]
StructureCompound #
(S. Singh)
SubstitutionDAT (IC50nM)
displacement of [H3]WIN 35428
5-HTT (IC50nM)
[H3]Citalopram
Selectivity
5-HTT/DAT
CocaineH65 ± 12--
Phenyltropane 103a.svg 103a3β,2β, 7-OMe
3′,4′-Cl2
86 ± 4.7884 ± 10010.3
Phenyltropane 103b.svg 103b3β,2β, 7-OH
3′,4′-Cl2
1.42 ± 0.0328.6 ± 7.820.1
Phenyltropane 103c.svg 103c3α,2β, 7-OH
3′,4′-Cl2
1.19 ± 0.161390 ± 561168
Phenyltropane 104a.svg 104a3β,2β, 6-OH
4′-Me
215ɑ--
Phenyltropane 104b.svg 104b3β,2α, 6-OH
4′-Me
15310ɑ--
Phenyltropane 104c.svg 104c3α,2β, 6-OH
4′-Me
930ɑ--
Phenyltropane 104d.svg 104d3α,2α, 6-OH
4′-Me
7860ɑ--

3-butyl 6/7 substituted

6/7-Substituted 3-butyl-phenyltropanes [1]
StructureCompound #
(S. Singh)
SubstituentKinM
displacement of [H3]mazindol binding
KinM
[H3]DA uptake
Selectivity
uptake/binding
CocaineH270 ± 0.03400 ± 201.5
Phenyltropane 121a.svg 121a7β-CN2020 ± 10710 ± 400.3
Phenyltropane 121b.svg 121b6β-CN3040 ± 4806030 ± 8802.0
Phenyltropane 121c.svg 121c7β-SO2Ph4010 ± 3108280 ± 13402.1
Phenyltropane 121d.svg 121d6β-SO2Ph4450 ± 4308270 ± 6901.8
Phenyltropane 121e.svg 121e7α-OH830 ± 40780 ± 600.9
Phenyltropane 121f.svg 121fH100 ± 1061 ± 100.6
Phenyltropane 121g.svg 121g7β-CN24000 ± 342032100 ± 85401.3
Phenyltropane 121h.svg 121h6β-CN11300 ± 154026600 ± 33302.3
Phenyltropane 121i.svg 121i7β-SO2Ph7690 ± 27707050 ± 4500.9
Phenyltropane 121j.svg 121j6β-SO2Ph4190 ± 7008590 ± 13602.0
Phenyltropane 121k.svg 121k7α-SO2Ph3420 ± 1100--
Phenyltropane 121l.svg 121l7β-SO2Ph, 7α-F840 ± 2602520 ± 2903.0
Phenyltropane 121m.svg 121m7α-F200 ± 10680 ± 103.4
Phenyltropane 121n.svg 121n7β-F500 ± 10550 ± 1401.1

intermediate 6- & 7-position synthesis modified phenyltropanes

6/7-synthetic intermediates [1]
StructureCompound #
(S. Singh)
Substituent WSubstituent XSubstituent YSubstituent Z
Phenyltropane 122a.svg (±)-122aCNHHH
Phenyltropane 122b.svg (±)-122bHHCHH
Phenyltropane 122c.svg (±)-122cHCHHH
Phenyltropane 122d.svg (±)-122dHHHCH
Phenyltropane 122e.svg (±)-122eSO2PhHHH
Phenyltropane 122f.svg (±)-122fHHSO2PhH
Phenyltropane 122g.svg (±)-122gHSO2PhHH
Phenyltropane 122h.svg (±)-122hSO2PhFHH
Phenyltropane 122i.svg (±)-122iFSO2PhHH
Phenyltropane 122j.svg (±)-122jHHSO2PhF

8-tropane (bridgehead) position modified

Nortropanes (N-demethylated)

NStwothreefivenine.png

NS2359 (GSK-372,475)

It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant. [33] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold. [34]

Selected ββ Nortropanes
Code
(S.S. #)
X
para
(unless position otherwise given inline)
DA5HTNE
RTI-142
75b
F4.3968.618.8
RTI-98
75d
Norɑ-RTI-55
I0.690.3611.0
RTI-110
75c
Cl0.624.135.45
RTI-173
75f
Et49.98.13122
RTI-279
Norɑ-RTI-280
para-Me
meta-I
5.98 ± 0.481.06 ± 0.1074.3 ± 3.8
RTI-305
Norɑ-RTI-360/11y
Ethynyl1.24 ± 0.111.59 ± 0.221.8 ± 1.0
RTI-307
Norɑ-RTI-281/11z
Propynyl6.11 ± 0.673.16 ± 0.33115.6 ± 5.1
RTI-309
Norɑ-11t
Vinyl1.73 ± 0.052.25 ± 0.1714.9 ± 1.18
RTI-330
Norɑ-11s
Isopropyl310.2 ± 2115.1 ± 0.97
RTI-353 para-Et
meta-I
330.54 ± 17.120.69 ± 0.07148.4 ± 9.15

ɑThe N-demethylated variant of (i.e. compound code-name after dash)

N-demethylating various β,β p-HC-phenyltropanes
N-Me compound code#

N-demethylated derivative
compound code #
para-X[3H]Paroxetine[3H]WIN 35,428[3H]Nisoxetine
11 g75f Ethyl 28.4 → 8.1355 → 49.94,029 → 122
11t75i Vinyl 9.5 → 2.251.24 → 1.7378 → 14.9
11y75n Ethynyl 4.4 → 1.591.2 → 1.2483.2 → 21.8
11r75 g1-Propyl70.4 → 2668.5 → 2123,920 → 532
11v75ktrans-propenyl 11.4 → 1.35.29 → 28.61,590 → 54
11w75lcis-propenyl7.09 → 1.1515 → 31.62,800 → 147
11x75 m Allyl 28.4 → 6.232.8 → 56.52,480 → 89.7
11z75o1-Propynyl 15.7 → 3.162.37 → 6.11820 → 116
11s75hi-Propyl191 → 15.1597 → 31075,000 → ?
11u75j2-Propenyl 3.13 → 0.614.4 → 231,330? → 144
N-Demethylating phenyltropanes to find a NRI
Isomer4′3′NEDA5HT
β,βMeH60 → 7.21.7 → 0.84240 → 135
β,βFH835 → 18.815.7 → 4.4760 → 68.6
β,βClH37 → 5.451.12 → 0.6245 → 4.13
β,αMeH270 → 910.2 → 33.64250 → 500
β,αFH1200 → 9.821 → 32.65060 → 92.4
β,αClH60 → 5.412.4 → 3.1998 → 53.3
β,αFMe148 → 4.2313.7 → 9.381161 → 69.8
β,αMeF44.7 → 0.867.38 → 91150 → 97.4

"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005). [35]

N-norphenyltropanes [1]
StructureShort Name
(S. Singh)
Para-XDAT
[3H]WIN 35428 IC50 (nM)
5-HTT
[3H]Paroxetine IC50 (nM)
NET
[3H]Nisoxetine IC50 (nM)
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
NorcocaineH206 ± 29127 ± 13139 ± 90.60.7
Singh 75a.svg 75aH30.8 ± 2.3156 ± 884.5 ± 7.55.12.7
Singh 75b.svg 75bF4.39 ± 0.2068.6 ± 2.018.8 ± 0.715.64.3
Singh 75c.svg 75cCl0.62 ± 0.094.13 ± 0.625.45 ± 0.216.78.8
Singh 75d.svg 75dI0.69 ± 0.20.36 ± 0.057.54 ± 3.190.510.9
Singh 75e.svg 75epara-I
&
2β-CO2CH(CH3)2
1.06 ± 0.123.59 ± 0.27132 ± 53.4124
Singh 75f.svg 75fC2H549.9 ± 7.38.13 ± 0.30122 ± 120.22.4
Singh 75g.svg 75gn-C3H7212 ± 1726 ± 1.3532 ± 8.10.12.5
Singh 75h.svg 75hCH(CH3)2310 ± 2115.1 ± 0.97-0.05-
Singh 75i.svg 75iCH=CH21.73 ± 0.052.25 ± 0.1714.9 ± 1.181.38.6
Singh 75j.svg 75jC-CH3

CH2
23 ± 0.90.6 ± 0.06144 ± 120.036.3
Singh 75k.svg 75ktrans-CH=CHCH328.6 ± 3.11.3 ± 0.154 ± 160.041.9
Singh 75l.svg 75lcis-CH=CHCH331.6 ± 2.21.15 ± 0.1147 ± 4.30.044.6
Singh 75m.svg 75mCH2CH=CH256.5 ± 566.2 ± 0.389.7 ± 9.60.11.6
Singh 75n.svg 75nCH≡CH1.24 ± 0.111.59 ± 0.221.8 ± 1.01.317.6
Singh 75o.svg 75oCH≡CCH36.11 ± 0.673.16 ± 0.33116 ± 5.10.519.0
Singh 75p.svg 75pɑ3,4-Cl20.66 ± 0.241.4b-2.1-

ɑThese values determined in Cynomolgus monkey caudate-putamenbThe radioligand used for 5-HTT was [3H]citalopram

2β-Propanoyl-N-norphenyltropanes [1]
Compound StructureShort Name
(S. Singh)
DAT
[125I]RTI-55 IC50 (nM)
5-HTT
[3H]Paroxetine Ki (nM)
NET
[3H]Nisoxetine Ki (nM)
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
Singh 79a.svg 79a0.07 ± 0.010.22 ± 0.162.0 ± 0.093.128.6
Singh 79b.svg 79b4.7 ± 0.5819 ± 1.45.5 ± 2.04.01.2
Singh 79c.svg 79c380 ± 1105.3 ± 1.03400 ± 2700.018.9
Singh 79d.svg 79d190 ± 17150 ± 505100 ± 2200.826.8
Singh 79e.svg 79e490 ± 12085 ± 164300 ± 11000.18.8
Singh 79f.svg 79f1.5 ± 1.10.32 ± 0.0610.9 ± 1.50.27.3
Singh 79g.svg 79g16 ± 4.90.11 ± 0.0294 ± 180.075.9

Paroxetine homologues

See the N-methyl paroxetine homologues cf. di-aryl phenyltropanes for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class.

2-(3,4-(Methylenedioxy)phenoxy)methyl-norphenyltropane binding potencies [1]
Compound StructureShort Name
(S. Singh)
StereochemistryDAT
[3H]WIN 35428 IC50 (nM)
5-HTT
[3H]Paroxetine IC50 (nM)
NET
[3H]Nisoxetine IC50 (nM)
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
Paroxetine-2D-skeletal.svg Paroxetine-623 ± 250.28 ± 0.02535 ± 150.00040.8
Singh 81a.svg R-81a2β,3β835 ± 90480 ± 2137400 ± 14000.644.8
Singh 81b.svg R-81b2α,3β142 ± 1390 ± 3.42500 ± 2500.617.6
Singh 81c.svg R-81c2β,3α3.86 ± 0.25.62 ± 0.214.4 ± 1.31.43.7
Singh 81d.svg S-81d2β,3β1210 ± 33424 ± 1517300 ± 18000.314.3
Singh 81e.svg S-81e2α,3β27.6 ± 2.455.8 ± 5.731690 ± 1502.061.2
Singh 81f.svg S-81f2β,3α407 ± 3319 ± 1.81990 ± 1760.054.9

N-replaced (S,O,C)

Phenyltropane R-97a.svg
R-97a (above) & S-97b (below), both examples of interm. synth. prod. in the R/S-90 & 91 series of phenyltropanes; showing the decay of the benzene structure during the synthetic process preceding the creation of like-series of PTs. [1]
Phenyltropane S-97b.svg

The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.

Tropoxane.png
Thia.png
CompoundX2 Groupconfig8DA5-HTNE
Tropoxane Cl,ClCO2Me(racemic) β,βO3.36.5No data
O-4210 [36] p-F3-methyl-5-isoxazoleβ,βS7.0>1000No data
Mid-synth stage in similar compound preparation as like to above. 10,10-dimethyl-4-((1R,5S)-8-methyl-8-azabicyclo(3.2.1)oct-2-ene-2-carbonyl)-3l6-thia-4-azatricyclo(5.2.1.01,5)decane-3,3-dione.svg
Mid-synth stage in similar compound preparation as like to above.
Meltzer.png

8-oxa bridgehead replacements

8-Oxanortropanes, binding inhibition using monkey caudate-putamen [1]
StructureCompound #
(S. Singh)
Para-
(meta-)
DAT (IC50nM)
displacement of [H3]WIN 35428
5-HTT (IC50nM)
[H3]Citalopram
Selectivity
5-HTT/DAT
Singh 90a.svg R/S-90aH>1000>1000-
Singh 90b.svg R/S-90bF54625804.7
Singh 90c.svg R/S-90cCl1010710.7
Singh 90d.svg R/S-90dBr22301.4
Singh 90e.svg R/S-90eI7121.7
Singh 90fg.svg R/S-90f3,4-Cl23.356.521.9
Singh 90fg.svg R-90g3,4-Cl23.274.671.4
Singh 90h.svg S-90h3,4-Cl247581.2
Singh 91a.svg R/S-91aH1990114405.7
Singh 91b.svg R/S-91bF>1000>10000-
Singh 91c.svg R/S-91cCl28.581628.6
Singh 91d.svg R/S-91dBr927630.7
Singh 91e.svg R/S-91eI42721.7
Singh 91fg.svg R/S-91f3,4-Cl23.0864.520.9
Singh 91fg.svg R-91g3,4-Cl22.343113.2
Singh 91h.svg S-91h3,4-Cl256286051.1

8-carba bridgehead replacements

8-carba 3-Aryl bicyclo[3.2.1]octanes [1]
StructureCompound #
(S. Singh)
DAT (IC50nM)
displacement of [H3]WIN 35428
5-HTT (IC50nM)
[H3]Citalopram
Selectivity
5-HTT/DAT
Phenyltropane analog 98a.svg R/S-98a7.1 ± 1.75160 ± 580726
Phenyltropane analog 98b.svg R/S-98b9.6 ± 1.833.4 ± 0.63.5
Phenyltropane analog 98c.svg R/S-98c14.3 ± 1.1180 ± 6512.6

N-alkyl

RTI-242 structure.png
Altropane.svg
Ioflupane.png
CompoundX2 Groupconfig8DATSERTNET
FP-β-CPPIT Cl3′-phenylisoxazol-5′-ylβ,βNCH2CH2CH2F---
FE-β-CPPIT Cl(3′-phenylisoxazol-5′-yl)β,βNCH2CH2F---
Altropane (IACFT)FCO2Meβ,βNCH2CH=CHF---
FECNT [37] ICO2Meβ,βNCH2CH2F---
RTI-310 U.S. patent 5,736,123 ICO2Meβ,βN-Prn1.17--
RTI-311 ICO2Meβ,βNCH2CH=CH21.79--
RTI-312 U.S. patent 5,736,123 ICO2Meβ,βNBun0.76--
RTI-313 U.S. patent 5,736,123 ICO2Meβ,βNCH2CH2CH2F1.67--
Ioflupane (FP-CIT)123ICO2Meβ,βNCH2CH2CH2F---
PE2I [37] MeCO2Meβ,βNCH2CH=CHI---
RTI-251 ClCO2Meβ,βNCH2CO2Et1.9310.1114
RTI-252 ClCO2Meβ,βNCH2CH2CO2Et2.5635.2125
RTI-242 Clβ,β (bridged) -C(O)CH(CO2Me)CH2N7.67227510

Bi- and tri-cyclic aza compounds and their uses. [38] [39]

N-substituted 3β-phenylnortropanes [1]
(including N-phthalimidoalkyl analogues of β-CIT)
StructureShort Name
(S. Singh)
Nitrogen side-chain
(N8)
DAT
[3H]GBR 12935 Ki (nM)
5-HTT
[3H]Paroxetine Ki (nM)
NET
[3H]Nisoxetine Ki (nM)
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
CocaineH350 ± 80>10000>30000>28.6-
GBR 12909-0.06 ± 0.0252.8 ± 4.4>20000880-
WIN 35428
11b
H14.7 ± 2.9181 ± 21635 ± 11012.343.2
RTI-55
11e
H1.40 ± 0.200.46 ± 0.062.80 ± 0.400.32
Singh 82a.svg 82aCH2CH=CH222.6 ± 2.9ɑ----
Singh 82b.svg 82bCH2CH2CH343.0 ± 17.7ɑ----
Singh 82c.svg 82cCH2C6H558.9 ± 1.65b1073c-18.2-
Singh 82d.svg 82d(CH2)3C6H51.4 ± 0.2b133 ± 7c-95.0-
Singh 82e.svg 82e(CH2)5C6H53.4 ± 0.83b49.9 ± 10.2c-14.7-
Singh 83a.svg 83aCH2CH2CH2F1.20 ± 0.2948.7 ± 8.41000040.68333
Singh 83b.svg 83bCH2CH2F4.40 ± 0.3521.7 ± 8.3>100004.9-
Singh 84a.svg 84aCH2CH2CH2F3.50 ± 0.390.110 ± 0.0263.0 ± 4.00.0318
Singh 84b.svg 84bCH2CH2F4.00 ± 0.730.140 ± 0.0293.0 ± 17.00.0323.2
Singh 84c.svg 84cCH2CHF215.1 ± 3.79.6 ± 1.5>50000.6-
Singh 84d.svg 84dCH2CH2CH2Cl3.10 ± 0.570.32 ± 0.0696.0 ± 29.00.131.0
Singh 84e.svg 84eCH2CH2CH2Br2.56 ± 0.570.35 ± 0.08164 ± 470.164.1
Singh 84f.svg 84fCH2CH2CH2I38.9 ± 6.38.84 ± 0.5350000.2128
Singh 84g.svg 84gCH2...methylcyclopropane4.30 ± 0.871.30 ± 0.25198 ± 9.60.346.0
Singh 84h.svg 84hCH2CH2CH2OH5.39 ± 0.212.50 ± 0.20217 ± 190.540.2
Singh 84i.svg 84iCH2CH2(OCH3)26.80 ± 1.101.69 ± 0.09110 ± 7.70.216.2
Singh 84j.svg 84jCH2CO2CH311.9 ± 1.40.81 ± 0.1029.1 ± 1.00.072.4
Singh 84k.svg 84kCH2CON(CH3)212.2 ± 3.86.40 ± 1.70522 ± 1450.542.8
Singh 84l.svg 84lCH2CH2CH2OMs36.3 ± 2.117.3 ± 1.250000.5138
Singh 84m.svg 84mCOCH(CH3)22100 ± 140102 ± 23>100000.05-
Singh 84n.svg 84n(CH2)2Pht4.23 ± 0.480.84 ± 0.02441 ± 66.00.2104
Singh 84o.svg 84o(CH2)3Pht9.10 ± 1.100.59 ± 0.0774.0 ± 11.60.068.1
Singh 84p.svg 84p(CH2)4Pht2.38 ± 0.220.21 ± 0.02190 ± 18.00.0979.8
Singh 84q.svg 84q(CH2)5Pht2.40 ± 0.170.34 ± 0.0360.0 ± 3.100.125.0
Singh 84r.svg 84r(CH2)8Pht2.98 ± 0.300.20 ± 0.0275.0 ± 3.60.0725.2
Singh 84s.svg 84sdCH2CH=CH-CH315 ± 175 ± 5400 ± 805.026.7
Singh 84t.svg 84tdCH2C(Br)=CH230 ± 5200 ± 40>10006.7-
Singh 84u.svg 84udCH2CH=CH2I(E)30 ± 5960 ± 60295 ± 3332.09.8
Singh 84v.svg 84vdCH2C≡CH14 ± 1100 ± 30>10007.1-
Singh 84w.svg 84wdCH2C6H542 ± 12100 ± 17600 ± 1002.414.3
Singh 84x.svg 84xdCH2C6H4-2-CH393 ± 19225 ± 40>10002.4-
Singh 85a.svg 85adpara-H113 ± 41100 ± 20>10000.9-
Singh 85b.svg 85bdpara-Cl, meta-Cl29 ± 450 ± 6500 ± 1201.717.2
Singh 85c.svg 85cdpara-Me17 ± 7500 ± 30>100029.4-
Singh 85d.svg 85ddpara-CH(CH3)2500 ± 120450 ± 80>10000.9-
Singh 85e.svg 85edpara-n-C3H7500 ± 100300 ± 12750 ± 1600.61.5
3β-(4-alkylthiophenyl)nortropanes [12]
Structure Di-subst thio sulfonyl nor-phenyltropanes.png CompoundR1R2Inhibition of [3H]WIN 35,428
@ DAT
IC50 (nM)
Inhibition of [3H]Paroxetine
@ 5-HTT
Ki (nM)
Inhibition of [3H]Nisoxetine
@ NET
Ki (nM)
NET/DAT
(uptake ratio)
NET/5-HTT
(uptake ratio)
See 7a—7h table
7aCH3CH39 ± 30.7 ± 0.2220 ± 1024314
7bC2H5CH3232 ± 344.5 ± 0.51170 ± 3005260
Phenyltropane 8a.svg 8aCH3H28 ± 60.19 ± 0.0121 ± 60.8110
Phenyltropane 8b.svg 8bC2H5H177 ± 621.26 ± 0.05118 ± 130.794
Phenyltropane 9a.svg 9aCH3FCH2CH2CH2112 ± 23 ± 1960 ± 1009320
Phenyltropane 9b.svg 9bC2H5FCH2CH2CH21,200 ± 20027 ± 2>2,000274
Phenyltropane 10a.svg 10aCH3CH2=CH2CH271 ± 255.5 ± 0.82,000 ± 50028364
Phenyltropane 10b.svg 10bC2H5CH2=CH2CH21,100 ± 10047 ± 3>2,000243
Phenyltropane 11a.svg 11aCH3CH3CH2CH274 ± 205.7 ± 0.61,200 ± 14016211
Phenyltropane 11b.svg 11bC2H5CH3CH2CH2900 ± 30049 ± 6>2,000241

Bridged N-constrained phenyltropanes (fused/tethered)

See: Bridged cocaine derivatives & N8 Tricyclic (2β—crossed-over) N8—to—3β replaced aryl linked (expansive front-bridged) cocaine analogues

p-methyl aryl front & back N-bridged phenyltropanes

U.S. patent 6,150,376

Structures mentioned in US6150376 table of Ki data. Koz US6150376.png
Structures mentioned in US6150376 table of Ki data.
Alternate 2D rendering of compound "42a" (from among the above 'bridged' phenyltropanes) to elucidate the potential overlaying structure of the place inhabited by the constrained nitrogen. Compare JNJ-7925476, tametraline and similar compounds. Alt2D-bridged-phenyltropane-no42a.png
Alternate 2D rendering of compound "42a" (from among the above 'bridged' phenyltropanes) to elucidate the potential overlaying structure of the place inhabited by the constrained nitrogen. Compare JNJ-7925476, tametraline and similar compounds.
RTI-242 RTI-4229-242.png
RTI-242
Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes Ki (nM)
Compound #
(S. Singh's #)
2β=R[3H]Mazindol binding[3H]DA uptake[3H]5-HT uptake[3H]NE uptakeselectivity
[3H]5-HT/[3H]DA
cocaineCO2CH3375 ± 68423 ± 147155 ± 4083.3 ± 1.50.4
(–)-40
(–)-128
54.3 ± 10.260.3 ± 0.41.76 ± 0.235.24 ± 0.070.03
(+)-40
(+)-128
79 ± 19114 ± 281.48 ± 0.074.62 ± 0.310.01
(±)-40
(±)-128
61.7 ± 8.560.3 ± 0.42.32 ± 0.232.69 ± 0.120.04
29β62014208030
30β18649297.7
31β47.021128.5
29α4140201003920
30α396088506961150
45
129
6.86 ± 0.4324.0 ± 1.31.77 ± 0.041.06 ± 0.030.07
42a
131a
n-Bu4.00 ± 0.072.23 ± 0.1214.0 ± 0.62.99 ± 0.176.3
41a
130a
n-Bu17.2 ± 1.1310.2 ± 1.478.9 ± 0.915.0 ± 0.47.8
42b
131b
Et3.61 ± 0.4311.3 ± 1.125.7 ± 4.34.43 ± 0.012.3
50a
133a
n-Bu149 ± 6149 ± 2810 ± 8051.7 ± 125.4
49a
132a
n-Bu13.7 ± 0.814.2 ± 0.1618 ± 873.84 ± 0.3543.5
(–)-41050016500189070900
(+)-41850027600463038300
(–)-597409050119004650
(+)-5677010500251004530
RTI-4229/Coc-242 N8/2β-C(O)CH(CO2Me)CH2N
para-chloro
7.67 ± 0.31ɑ226.54 ± 27.37b510.1 ± 51.4c
  • ɑValue for displacement of [3H]WIN 35,428 binding @ DAT
  • bValue for displacement of [3H]paroxetine binding to SERT
  • cValue for displacement of [3H]nisoxetine from NET

Fused tropane-derivatives as neurotransmitter reuptake inhibitors. Singh notes that all bridged derivatives tested displayed 2.5—104 fold higher DAT affinity than cocaine. The ones 2.8—190 fold more potent at DAT also had increased potency at the other two MAT sites (NET & SERT); NET having 1.6—78× increased activity. (+)-128 additionally exhibited 100× greater potency @ SERT, whereas 132a & 133a had 4—5.2× weaker 5-HTT (i.e. SERT) activity. Front-bridged (e.g. 128 & 129) had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged (e.g. 130—133) preferred placement with DAT interaction. [1] U.S. patent 5,998,405

3,4-Cl2 aryl front-bridged phenyltropanes

Fused Tropane: NeuroSearch A/S, Scheel-Kruger et al. U.S. patent 5,998,405 Fused Tropane.png
Fused Tropane: NeuroSearch A/S, Scheel-Krüger et al. U.S. patent 5,998,405
Frontbridged phenyltropane synthesis intermediate product compound #140 Phenyltropane 140.svg
Frontbridged phenyltropane synthesis intermediate product compound #140
CodeCompoundDA (μM)NE (μM)5-HT (μM)
1(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11 -one O-methyl-oxime0.0120.00200.0033
2(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-one0.180.0350.0075
3(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime0.01600.00090.0032
4(1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-ol0.07500.00410.0028
5(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one0.120.00520.0026
6(1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]-decan-5-ol0.250.00740.0018
7(1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]dec- 5-yl acetate0.210.00610.0075
8(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo[5.3.0.04,8]decane0.0220.00140.0001
  1. 1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes.
  2. 2° amine is reacted with Br(CH2)nCO2Et.
  3. Base used to abstract proton α- to CO2Et group and complete the tricyclic ring closure step (Dieckmann cyclization).

To make a different type of analog (see Kozikowski patent above)

  1. Remove N-Me
  2. Add ɣ-bromo-chloropropane
  3. Allow for cyclization with K2CO3 base and KI cat.

C2 + C3 (side-chain) fused (carboxylate & benzene conjoined)

Nitrogen-front-bridged indole phenyltropane. (3S,5S,8R)-3-(4-methylphenyl)-9,18-diazapentacyclo(9.7.0.02,8.05,9.012,17)octadeca-1(11),12(17),13,15-tetraene.svg
Nitrogen-front-bridged indole phenyltropane.

(1R,2S,10R,12S)-15-methyl-15-azatetracyclo(10.2.1.02,10.04,9)pentadeca-4(9),5,7-trien-3-one.svg
(1R,2S,10R,12S)-15-methyl-15-azatetracyclo(10.2.1.02,10.04,9)pentadeca-4(9),5,7-trien-3-one [3]

C3 to 1′ + 2′ (ortho) tropane locant dual arene bridged

Spirocyclic cocaine analog.svg
Parent compound of a series of spirocyclic cocaine benzoyl linkage modification analogs created by Suzuki coupling method of ortho-substituted arylboronic acids and an enol-triflate derived from cocaine; which technically has the three methylene length of cocaine analogues as well as the single length which defines the phenyltropane series. Note that the carbomethoxyl group is (due to constraints in synthetic processes used in the creation of this compound) alpha configured; which is not the usual, most prevalent, conformation favored for the PT cocaine-receptor binding pocket of most such sub-type of chemicals. The above and below depictions show attested compounds synthesized, additionally with variations upon the Endo–exo isomerism of their structures. [40]
Spirocyclic cocaine analog 12.svg

Cycloalkane-ring alterations of the tropane ring system

Azanonane (outer ring extended)

3-Phenyl-9-azabicyclo[3.3.1]nonane derivatives

To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs. [lower-alpha 9] Which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol.

Despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. Though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. Instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below.

[3.3.1]azanonane analogues
displacement of bound [3H]WIN 35428 [1]
StructureCompound #
(S. Singh)
Ki (nM)
Kokain - Cocaine.svg
Cocaine32 ± 5
390 ± 220
WIN 35,065-2.svg
WIN 35065-233 ± 17
310 ± 220
Cocaine analog 146a.svg
146a4600 ± 510
Cocaine analog 146b.svg
146b5730 ± 570
Cocaine analog 146c.svg
146c3450 ± 310
Cocaine analog 146d.svg
146d3470 ± 350
Cocaine analog 147.svg
14713900 ± 2010

Azabornane (outer ring contracted)

3-Phenyl-7-azabicyclo[2.2.1]heptane derivatives

Ring-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on MAT for an affinity in the efficacious range. The distance from the nitrogen to the phenyl centroid for 155a was 4.2 and 155c was 5.0 Å, respectively. (Whereas troparil was 5.6 & compound 20a 5.5 angstroms). However piperidine homologues (discussed below) had comparable potencies. [lower-alpha 10]

2-exo-phenyl-7-azabicyclo[2.2.1]heptane:

The non-carboxylic (and DAT substrate, releasing agent) variant of exo-2-phenyl-7-azabicyclo(2.2.1)heptane-1-carboxylic acid (N.B. the carboxy in the latter shares the C1 tropane position with the two carbon nitrogen containing bridge; sharing in the leftmost (R) substitution of the above depiction & unlike the placement on the tropane for either the carbmethoxy or phenyl ring of the azabornane analogues given in this section)

With the carboxy ester function removed the resultant derived compound acts as a DAT substrate drug, thus an amphetaminergic releaser of MAT & VMAT, yet similar to phenyltropanes (that usually are only re-uptake ligands) cf. EXP-561 & BTQ. 2-exo-phenyl-7-azabicyclo(2-2-1)heptane.png
2-exo-phenyl-7-azabicyclo[2.2.1]heptane:

The non-carboxylic (and DAT substrate, releasing agent) variant of exo-2-phenyl-7-azabicyclo(2.2.1)heptane-1-carboxylic acid (N.B. the carboxy in the latter shares the C1 tropane position with the two carbon nitrogen containing bridge; sharing in the leftmost (R) substitution of the above depiction & unlike the placement on the tropane for either the carbmethoxy or phenyl ring of the azabornane analogues given in this section)

With the carboxy ester function removed the resultant derived compound acts as a DAT substrate drug, thus an amphetaminergic releaser of MAT & VMAT, yet similar to phenyltropanes (that usually are only re-uptake ligands)
cf. EXP-561 & BTQ.

Azabornanes with longer substitutions at the 3β-position (benzoyloxys alkylphenyls, carbamoyls etc.) or with the nitrogen in the position it would be on the piperidine homologues (i.e. arrangements of differing locations for the nitrogens being either distal or proximal within the terms required to facilitate the framework of the compound to a correlative proportion, functional for the given moiety), were not synthesized, despite conclusions that the nitrogen to phenyl length was the issue at variance enough to be the interfering factor for the proper binding of the compressed topology of the azabornane. Carroll, however, has listed benzoyloxy azabornanes in patents. [3]

[2.2.1]azabornane analogues
displacement of bound [3H]WIN 35428 [1]
StructureCompound #
(S. Singh)
Ki (nM)
Kokain - Cocaine.svg
Cocaine32 ± 5
390 ± 220
WIN 35,065-2.svg
WIN 35065-233 ± 17
310 ± 220
Cocaine analog 155a.svg
155a60,400 ± 4,800
Cocaine analog 155b.svg
Cocaine analog 155b alt.svg
155b96,500 ± 42
Cocaine analog 155c.svg
155c5,620 ± 390
Cocaine analog 155d.svg
155d18,900 ± 1,700

Piperidine homologues (inner two-carbon bridge excised)

Piperidine homologues had comparable affinity & potency spreads to their respective phenyltropane analogues. Without as much of a discrepancy between the differing isomers of the piperidine class with respect to affinity and binding values as had in the phenyltropanes.

Phenyltropane 4-aryl-3-carboalkoxy-piperidine analogues [1]
StructureCompound #
(S. Singh)
X = para- / 4′-
Substitution
R = 2-tropane positionDAT (IC50nM)
[H3]WIN 35428 binding displacement
DA (IC50nM)
[H3]DA uptake
Selectivity
Uptake/Binding
Kokain - Cocaine.svg
CocaineHCO2Me102 ± 9239 ± 12.3
Cocaine analog 166a.svg
(±)-166aClβ-CO2CH353.7 ± 1.937.8 ± 7.90.7
(-)-166aClβ-CO2CH324.8 ± 1.685.2 ± 2.63.4
(+)-166aClβ-CO2CH31360 ± 1255090 ± 1723.7
Cocaine analog 167a.svg
(-)-167aClβ-CO2OH75.3 ± 6.249.0 ± 3.00.6
(+)-167aClβ-CO2OH442 ± 32
Cocaine analog 168a.svg
(-)-168aClβ-CO2OAc44.7 ± 10.562.9 ± 2.71.4
(+)-168aClβ-CO2OAc928 ± 432023 ± 822.2
Cocaine analog 169a.svg
(-)-169a [42] Clβ-n-Pr3.0 ± 0.58.3 ± 0.62.8
Cocaine analog 170a.svg
(-)-170aHβ-CO2CH3769 ± 19
Cocaine analog 166b.svg
(±)-166bClα-CO2CH3197 ± 8
(+)-166bClα-CO2CH357.3 ± 8.134.6 ± 3.20.6
(-)-166bClα-CO2CH3653 ± 38195 ± 80.3
Cocaine analog 167b.svg
(+)-167bClα-CO2OH240 ± 18683 ± 472.8
Cocaine analog 168b.svg
(+)-168bClα-CO2OAc461 ± 11
Cocaine analog 169b.svg
(+)-169bClα-n-Pr17.2 ± 0.523.2 ± 2.21.3

Heterocyclic N-Desmethyl [43]
4-(4-Chloro-phenyl)-3-(3-methyl-(1,2,4)oxadiazol-5-yl)-piperidine.png

Activity @ MAT for piperidine homologues of phenyltropanes, including naphthyl derivatives [44]
StructureCompound #[H3]DA uptake (nM)
IC50
[H3]DA uptake (nM)
Ki
[H3]NE uptake (nM)
IC50
[H3]NE uptake (nM)
Ki
[H3]5-HTT uptake (nM)
IC50
[H3]5-HTT uptake (nM)
Ki
Uptake Ratio
DA/5-HT (Ki)
Uptake Ratio
NE/5-HT (Ki)
Kokain - Cocaine.svg
Cocaine459 ± 159423 ± 147127 ± 4.1108 ± 3.5168 ± 0.4155 ± 0.42.70.69
Fluoxetine2DACS.svg
Fluoxetine>4500>2500193 ± 4.1176 ± 3.58.1 ± 0.77.3 ± 0.762424
Cocaine analog Tamiz 20.svg
2075 ± 9.169 ± 8.1101 ± 3.388 ± 2.9440 ± 30391 ± 270.180.23
Cocaine analog Tamiz 6.svg
623 ± 1.021 ± 0.9-34 ± 0.88.2 ± 0.37.6 ± 0.22.84.5
Cocaine analog Tamiz 7.svg
7>1000947 ± 135-241 ± 1.78.2 ± 0.37.6 ± 0.222.65.7
Cocaine analog Tamiz 8.svg
894 ± 9.687 ± 8.9-27 ± 1.6209 ± 17192 ± 160.450.14
Cocaine analog Tamiz 9.svg
9293 ± 6.4271 ± 5.9-38 ± 4.013 ± 0.712 ± 0.7233.2
Cocaine analog Tamiz 19.svg
1997 ± 8.690 ± 8.034 ± 2.530 ± 2.33.9 ± 0.53.5 ± 0.5268.6
Cocaine analog Tamiz 10.svg
10326 ± 1.2304 ± 1.1337 ± 37281 ± 30113 ± 4.3101 ± 3.83.02.8
Cocaine analog Tamiz 14.svg
14144 ± 20131 ± 18204 ± 5.6175 ± 4.8155 ± 3.9138 ± 3.50.951.3
Cocaine analog Tamiz 15.svg
15>1800>1700>1300>1100275 ± 39255 ± 37>6>4
Cocaine analog Tamiz 16.svg
16>1000964 ± 100>1200>1000334 ± 48309 ± 443.13.5
Cocaine analog Tamiz 17.svg
17213 ± 30187 ± 26399 ± 12364 ± 9.2189 ± 37175 ± 341.12.1
Cocaine analog Tamiz 18.svg
18184 ± 30173 ± 26239 ± 42203 ± 3667 ± 4.562 ± 4.12.83.3

distal-nitrogen 'dimethylamine' (piperidine-like cyclohexyl homologues of phenyltropanes) [3]

Ring opened phenyltropane analog A.svg Ring opened phenyltropane analog B.svg Ring opened phenyltropane analog C.svg
cf. Fencamfamine

Radiolabeled

Radiolabel Tropane: Page 64. G.A. Whitlock et al. Table 1 Potential SRI PET and SPECT ligands. Radiolabel Tropane.png
Radiolabel Tropane: Page 64. G.A. Whitlock et al. Table 1 Potential SRI PET and SPECT ligands.
LBT-999, a radio-ligand. LBT-999.svg
LBT-999, a radio-ligand.
CodeSERT Ki (nM)NET Ki (nM)DAT Ki (nM)RadiolabelIn vivo studyRefs.
10.2102.229.9 11C Non-human primate [46]
20.231.732.6 11C Non-human primate [47]
30.05243.47 123I Rat [48]
40.082813 18F Non-human primate [49]
50.1145022 11C Rat, monkey [50]
IPT (N-3-iodoprop-(2E)-ene-2b-carbomethoxy-3b-(4'-chlorophenyl)tropane), can be radiolabeled with I or I and used as a ligand to map several MATs N-3-iodoprop-(2E)-ene-2b-carbomethoxy-3b-(4'-chlorophenyl)tropane.png
IPT (N-3-iodoprop-(2E)-ene-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane), can be radiolabeled with I or I and used as a ligand to map several MATs
N-4-Fluorobut-2-yn-1-yl-2b-carbomethoxy-3b-phenyltropane (PR04.MZ) often radiolabeled. N-4-Fluorobut-2-yn-1-yl-2b-carbomethoxy-3b-phenyltropane.png
N-4-Fluorobut-2-yn-1-yl-2β-carbomethoxy-3β-phenyltropane (PR04.MZ) often radiolabeled.
JHC1-64. A fluorescent analog, similar in its long chain off of the nitrogen bridge similar to the transition metal phenyltropane types. JHC 1-64.svg
JHC1-64. A fluorescent analog, similar in its long chain off of the nitrogen bridge similar to the transition metal phenyltropane types.

Transition metal complexes

These compounds include transition metals in their heteroatomic conformation, unlike non-radiolabel intended chelates where their element is chosen for intrinsic affectation to binding and function, these are tagged on by a "tail" (or similar) with a sufficient spacer to remain separated from known binding properties and instead are meant to add radioactivity enough to be easily tracked via observation methods that utilize radioactivity. As for anomalies of binding within the spectrum of the under-written kinds just mentioned: other factors not otherwise considered to account for its relatively lower potency, "compound 89c" is posited to protrude forward at the aryl place on its moiety toward the MAT ligand acceptor site in a manner detrimental to its efficacy. That is considered due to the steric bulk of the eight-position "tail" chelate substituted constituent, overreaching the means by which it was intended to be isolated from binding factors upon a tail, and ultimately nonetheless, interfering with its ability to bind. However, to broach this discrepancy, decreasing of the nitrogen tether at the eight position by a single methylene unit (89d) was shown to bring the potency of the analogous compound to the expected, substantially higher, potency: The N-methyl analog of 89c having an IC50 of 1.09 ± 0.02 @ DAT & 2.47 ± 0.14 nM @ SERT; making 89c upwards of thirty-three times weaker at those MAT uptake sites. [lower-alpha 11]

"Transition metal" chelated phenyltropanes [1]
StructureCompound #
(S. Singh)
X = para- / 4′-
Substitution
ConfigurationDAT (IC50nM)
displacement of [H3]WIN 35428
5-HTT (IC50nM)
[H3]Citalopram
Selectivity
5-HTT/DAT
Phenyltropane 11b - WIN 35428.svg
WIN 35428F-11.0 ± 1.0160 ± 2014.5
+2β-chelated phenyltropanes
Cocaine analog 73 - TRODAT-1.svg
73
TRODAT-1ɑ
Cl-R=13.9, S=8.42b--
Cocaine analog 74 - TROTEC-1.svg
74
TROTEC-1
F-high affinity site = 0.15 ± 0.04c
low affinity site = 20.3 ± 16.1c
--
N-chelated phenyltropanes
Cocaine analog 89a.svg
89aF5.99 ± 0.81124 ± 1720.7
Cocaine analog 89b.svg
89bF2960 ± 1575020 ± 18801.7
Cocaine analog 89c.svg
89c3,4-Cl237.2 ± 3.4264 ± 167.1
Cocaine analog 89d.svg
89dCl-0.31 ± 0.03d--

Select annotations of above

Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.
Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. U.S. patent 6,329,520 , U.S. patent 7,011,813 , U.S. patent 6,531,483 , and U.S. patent 7,291,737 .

Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug that is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT binding affinity.

Sister substances

Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine class (a category that includes methylphenidate) or benztropine class (such as Difluoropine: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.

Most any variant with a tropane locant—3-β (or α) connecting linkage differing from, e.g. longer than, a single methylene unit (i.e. "phenyl"), including alkylphenyls (see the styrene analog, first image given in example below) is more correctly a "cocaine analogue" proper, and not a phenyltropane. Especially if this linkage imparts a sodium channel blocker functionality to the molecule.

See also

Related Research Articles

<span class="mw-page-title-main">WIN-35428</span> Chemical compound

(–)-2-β-Carbomethoxy-3-β-(4-fluorophenyl)tropane is a stimulant drug used in scientific research. CFT is a phenyltropane based dopamine reuptake inhibitor and is structurally derived from cocaine. It is around 3-10x more potent than cocaine and lasts around 7 times longer based on animal studies. While the naphthalenedisulfonate salt is the most commonly used form in scientific research due to its high solubility in water, the free base and hydrochloride salts are known compounds and can also be produced. The tartrate is another salt form that is reported.

<span class="mw-page-title-main">Phenyltropane</span> Class of chemical compounds

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

<span class="mw-page-title-main">(+)-CPCA</span> Stimulant drug

(+)-CPCA is a stimulant drug similar in structure to pethidine and to RTI-31, but nocaine is lacking the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.

<span class="mw-page-title-main">Troparil</span> Chemical compound

Troparil is a stimulant drug used in scientific research. Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine. Troparil is a few times more potent than cocaine as a dopamine reuptake inhibitor, but is less potent as a serotonin reuptake inhibitor, and has a duration spanning a few times longer, since the phenyl ring is directly connected to the tropane ring through a non-hydrolyzable carbon-carbon bond. The lack of an ester linkage removes the local anesthetic action from the drug, so troparil is a pure stimulant. This change in activity also makes troparil slightly less cardiotoxic than cocaine. The most commonly used form of troparil is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.

<span class="mw-page-title-main">RTI-55</span> Chemical compound

RTI(-4229)-55, also called RTI-55 or iometopane, is a phenyltropane-based psychostimulant used in scientific research and in some medical applications. This drug was first cited in 1991. RTI-55 is a non-selective dopamine reuptake inhibitor derived from methylecgonidine. However, more selective analogs are derived by conversion to "pyrrolidinoamido" RTI-229, for instance. Due to the large bulbous nature of the weakly electron withdrawing iodo halogen atom, RTI-55 is the most strongly serotonergic of the simple para-substituted troparil based analogs. In rodents RTI-55 actually caused death at a dosage of 100 mg/kg, whereas RTI-51 and RTI-31 did not. Another notable observation is the strong propensity of RTI-55 to cause locomotor activity enhancements, although in an earlier study, RTI-51 was actually even stronger than RTI-55 in shifting baseline LMA. This observation serves to highlight the disparities that can arise between studies.

<span class="mw-page-title-main">2β-Propanoyl-3β-(2-naphthyl)-tropane</span> Chemical compound

2β-Propanoyl-3β-(2-naphthyl)-tropane or WF-23 is a cocaine analogue. It is several hundred times more potent than cocaine at being a serotonin-norepinephrine-dopamine reuptake inhibitor.

<span class="mw-page-title-main">Dichloropane</span> Chemical compound

Dichloropane ((−)-2β-Carbomethoxy-3β-(3,4-dichlorophenyl)tropane, RTI-111, O-401) is a stimulant of the phenyltropane class that acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) with IC50 values of 3.13, 18, and 0.79 nM, respectively. In animal studies, dichloropane had a slower onset and longer duration of action compared to cocaine.

<span class="mw-page-title-main">RTI-126</span> Pharmaceutical drug

RTI-126 is a phenyltropane derivative which acts as a potent monoamine reuptake inhibitor and stimulant drug, and has been sold as a designer drug. It is around 5 times more potent than cocaine at inhibiting monoamine reuptake in vitro, but is relatively unselective. It binds to all three monoamine transporters, although still with some selectivity for the dopamine transporter. RTI-126 has a fast onset of effects and short duration of action, and its pharmacological profile in animals is among the closest to cocaine itself out of all the drugs in the RTI series. Its main application in scientific research has been in studies investigating the influence of pharmacokinetics on the abuse potential of stimulant drugs, with its rapid entry into the brain thought to be a key factor in producing its high propensity for development of dependence in animals.

<span class="mw-page-title-main">RTI-336</span> Chemical compound

RTI(-4229)-336, is a phenyltropane derivative which acts as a potent and selective dopamine reuptake inhibitor and stimulant drug. It binds to the dopamine transporter with around 20x the affinity of cocaine, however it produces relatively mild stimulant effects, with a slow onset and long duration of action. These characteristics make it a potential candidate for treatment of cocaine addiction, as a possible substitute drug analogous to how methadone is used for treating heroin abuse. RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration, and significantly reduces rates of cocaine use, especially when combined with SSRIs, and research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.

<span class="mw-page-title-main">RTI-113</span> Chemical compound

RTI(-4229)-113 is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor (DRI). It has been suggested as a possible substitute drug for the treatment of cocaine addiction. "RTI-113 has properties that make it an ideal medication for cocaine abusers, such as an equivalent efficacy, a higher potency, and a longer duration of action as compared to cocaine." Replacing the methyl ester in RTI-31 with a phenyl ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant phenyltropane cocaine analog that has been tested on squirrel monkeys. RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys. The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.

<span class="mw-page-title-main">RTI-177</span> Chemical compound

RTI(-4229)-177 is a synthetic stimulant drug from the phenyltropane family, which acts as a DRI with micromolar affinity for the SERT. RTI-177 has an unusually long duration of action of 20 hours or more, substantially longer than the related compound RTI-336 from which it differs in molecular structure only by the absence of a p-methyl group.

<span class="mw-page-title-main">RTI-31</span> Chemical compound

(–)-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane (RTI-4229-31) is a synthetic analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article, RTI-31 is 64 times the strength of cocaine in terms of its potency to elicit self-administration in monkeys. WIN 35428 was 6 times weaker than RTI-31, whereas RTI-51 was 2.6 times weaker than RTI-31.

<span class="mw-page-title-main">RTI-51</span> Chemical compound

(–)-2β-Carbomethoxy-3β-(4-bromophenyl)tropane is a semi-synthetic alkaloid in the phenyltropane group of psychostimulant compounds. First publicized in the 1990s, it has not been used enough to have gained a fully established profile. RTI-51 can be expected to have properties lying somewhere in between RTI-31 and RTI-55. It has a ratio of monoamine reuptake inhibition of dopamine > serotonin > norepinephrine which is an unusual balance of effects not produced by other commonly used compounds. It has been used in its 76Br radiolabelled form to map the distribution of dopamine transporters in the brain.

<span class="mw-page-title-main">RTI-32</span> Chemical compound

(–)-2β-Carbomethoxy-3β-(4-tolyl)tropane is a phenyltropane-based cocaine analogue that has similar properties in vitro to related drugs such as RTI-31.

<span class="mw-page-title-main">RTI-274</span> Chemical compound

RTI(-4229)-274, or 2β-( methyl)-3α-(4-fluorophenyl)​nortropane is a phenyltropane homologue of paroxetine developed by the group led by F Ivy Carroll in the 1990s.

<span class="mw-page-title-main">Salicylmethylecgonine</span> Chemical compound

Salicylmethylecgonine, (2′-Hydroxycocaine) is a tropane derivative drug which is both a synthetic analogue and a possible active metabolite of cocaine. Its potency in vitro is around 10x that of cocaine, although it is only around three times more potent than cocaine when administered to mice Note however that the compound 2′-Acetoxycocaine would act as a prodrug to Salicylmethylecgonine in humans, and has a more efficient partition coefficient which would act as a delivery system and would circumvent this reason for a drop in potency. Salicylmethylecgonine also shows increased behavioral stimulation compared to cocaine similar to the phenyltropanes. The hydroxy branch renders the molecule a QSAR of a 10-fold increase over cocaine in its binding potency for the dopamine transporter & a 52-fold enhanced affinity for the norepinephrine transporter. It also has a reduced selectivity for the serotonin transporter though only due to its greater increase at NET binding; its SERT affinity being 4-fold increased compared to cocaine. However, in overall binding affinity it displaces ligands better across the board than cocaine in all monoamine categories.

<span class="mw-page-title-main">RTI-229</span> Chemical compound

RTI-229, also known as (–)-3β-(4-iodophenyl)tropane-2β-pyrrolidine carboxamide and RTI-4229-229, is a potent and long-lasting stimulant drug which was developed in the 1990s as part of a large group of related analogues from the phenyltropane family. With the combination of two potent dopamine transporter (DAT) binding motifs attached to the tropane ring, the p-iodophenyl group at the 3β-position and a pyrrolidine carboxamide at 2β, RTI-229 has extremely high selectivity for the dopamine transporter and is one of the most DAT-selective compounds in the RTI series.

<span class="mw-page-title-main">RTI-120</span> Chemical compound

(–)-2β-Carbophenoxy-3β-(p-tolyl)tropane (RTI-4229-120) is a phenyltropane derivative which acts as a reasonably selective dopamine reuptake inhibitor, along with weaker inhibition of noradrenaline and serotonin reuptake. It has a reasonably fast rate of occupancy of dopamine transporters in the brain, though slower than that of cocaine itself. RTI-120 has a short duration of action, along with other p-methyl substituted phenyltropanes such as RTI-150, RTI-171 and RTI-199, giving it a more similar pharmacological profile to cocaine compared to longer acting analogues like RTI-121 and RTI-177.

<span class="mw-page-title-main">RTI-83</span> Chemical compound

RTI-83 is a phenyltropane derivative which represents a rare example of an SDRI or serotonin-dopamine reuptake inhibitor, a drug which inhibits the reuptake of the neurotransmitters serotonin and dopamine, while having little or no effect on the reuptake of the related neurotransmitter noradrenaline. With a binding affinity (Ki) of 55 nM at DAT and 28.4 nM at SERT but only 4030 nM at NET, RTI-83 has reasonable selectivity for DAT/SERT over NET

References

Citations

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Singh, Satendra (2000). "Chem Inform Abstract: Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists" (PDF). ChemInform. 31 (20): no. doi:10.1002/chin.200020238. Mirror hotlink.
  2. U.S. Patent Application Publication # US 2008/0153870 A1 M. J. Kuhar, et al. Jun. 26, 2008. Research Triangle Institute.
  3. 1 2 3 4 5 6 7 8 9 10 U.S. patent 6,479,509
  4. 1 2 3 Tamagnan, Gilles (2005). "Synthesis and monoamine transporter affinity of new 2β-carbomethoxy-3β-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency". Bioorganic & Medicinal Chemistry. 15 (4): 1131–1133. doi:10.1016/j.bmcl.2004.12.014. PMID   15686927.
  5. Schmitt, K. C.; Rothman, R. B.; Reith, M. E. (Jul 2013). "Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates". J Pharmacol Exp Ther. 346 (1): 2–10 Fig. 1. doi:10.1124/jpet.111.191056. PMC   3684841 . PMID   23568856.
  6. U.S. patent 6,479,509 Method of promoting smoking cessation.
  7. Blough, B. E.; Keverline, K. I.; Nie, Z.; Navarro, H.; Kuhar, M. J.; Carroll, F. I. (2002). "Synthesis and transporter binding properties of 3β-4′-(phenylalkyl, -phenylalkenyl, and -phenylalkynyl)phenyltropane-2β-carboxylic acid methyl esters: evidence of a remote phenyl binding domain on the dopamine transporter". Journal of Medicinal Chemistry . 45 (18): 4029–4037. doi:10.1021/jm020098n. PMID   12190324.
  8. 1 2 Blough, Bruce E.; Keverline, Kathryn I.; Nie, Zhe; Navarro, Hernán; Kuhar, Michael J.; Carroll, F. Ivy (2002). "Synthesis and Transporter Binding Properties of 3β-[4'-(Phenylalkyl, -phenylalkenyl, and -phenylalkynl)phenyl]tropane-2β-carboxylic Acid Methyl Esters: Evidence of a Remote Phenyl Binding Domain on the Dopamine Transporter". Journal of Medicinal Chemistry. 45 (18): 4029–37. doi:10.1021/jm020098n. PMID   12190324.
  9. Blough; et al. (Sep 1996). "Synthesis and transporter binding properties of 3β-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 β-carboxylic acid methyl esters: serotonin transporter selective analogs". J Med Chem. 39 (20): 4027–35. doi:10.1021/jm960409s. PMID   8831768. S2CID   21616809.
  10. 1 2 Meltzer, P. C.; Liang, A. Y.; Brownell, A. L.; Elmaleh, D. R.; Madras, B. K. (1993). "Substituted 3-phenyltropane analogs of cocaine: Synthesis, inhibition of binding at cocaine recognition sites, and positron emission tomography imaging". Journal of Medicinal Chemistry. 36 (7): 855–62. doi:10.1021/jm00059a010. PMID   8464040.
  11. 1 2 Meltzer, P. C.; McPhee, M.; Madras, B. K. (2003). "Synthesis and biological activity of 2-Carbomethoxy-3-catechol-8-azabicyclo[3.2.1]octanes". Bioorganic & Medicinal Chemistry Letters. 13 (22): 4133–4137. doi:10.1016/j.bmcl.2003.07.014. PMID   14592523.
  12. 1 2 Jin, Chunyang; Navarro, Hernán A.; Ivy Carroll, F. (2009). "Synthesis and structure–activity relationship of 3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane and 3β-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters". Bioorganic & Medicinal Chemistry. 17 (14): 5126–5132. doi:10.1016/j.bmc.2009.05.052. ISSN   0968-0896. PMC   2747657 . PMID   19523837.
  13. R. H. Kline, Davies, E. Saikali, T. Sexton & S.R. Childers (1993). "Novel 2-substituted cocaine analogs: Binding properties at dopamine transport sites in rat striatum". European Journal of Pharmacology. 244 (1): 93–97. doi:10.1016/0922-4106(93)90063-f. PMID   8420793.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. Jin, C; Navarro, H. A.; Carroll, F. I. (2008). "Development of 3-Phenyltropane Analogs with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter". Journal of Medicinal Chemistry. 51 (24): 8048–8056. doi:10.1021/jm801162z. PMC   2841478 . PMID   19053748. Table 1.
  15. Jin, C; Navarro, H. A.; Carroll, F. I. (2008). "Development of 3-Phenyltropane Analogs with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter". Journal of Medicinal Chemistry. 51 (24): 8048–8056. doi:10.1021/jm801162z. PMC   2841478 . PMID   19053748. Table 2.
  16. Zhong, Desong; Kotian, Pravin; Wyrick, Christopher D.; Seltzman, Herbert H.; Kepler, John A.; Kuhar, Michael J.; Boja, John W.; Carroll, F. Ivy (1999). "Synthesis of 3β-(4-[125I]iodophenyl)tropane-2-β-pyrrolidine carboxamide ([125I]RTI-229)". Journal of Labelled Compounds and Radiopharmaceuticals. 42 (3): 281–286. doi:10.1002/(SICI)1099-1344(199903)42:3<281::AID-JLCR188>3.0.CO;2-X.
  17. Carroll, F. I.; Gray; Abraham; Kuzemko; Lewin; Boja; Kuhar (1993). "3-Aryl-2-(3′-substituted-1′,2′,4'-oxadiazol-5′-yl)tropane analogues of cocaine: affinities at the cocaine binding site at the dopamine, serotonin, and norepinephrine transporters". Journal of Medicinal Chemistry . 36 (20): 2886–2890. doi:10.1021/jm00072a007. PMID   8411004.
  18. 1 2 Methods for controlling invertebrate pests using cocaine receptor binding ligands. U.S. patent 5,935,953
  19. Carroll, F.; Howard, J.; Howell, L.; Fox, B.; Kuhar, M. (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS Journal. 8 (1): E196–E203. doi:10.1208/aapsj080124. PMC   2751440 . PMID   16584128.
  20. Carroll, F.; Howard, J.; Howell, L.; Fox, B.; Kuhar, M. (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS Journal. 8 (1): E196–E203. doi:10.1208/aapsj080124. PMC   2751440 . PMID   16584128.
  21. Davies, Huw M.L; Ren, Pingda; Kong, Norman; Sexton, Tammy; Childers, Steven R (2001). "Synthesis and monoamine transporter affinity of 3β-(4-(2-pyrrolyl)phenyl)-8-azabicyclo[3.2.1]octanes and 3β-(5-Indolyl)-8-azabicyclo[3.2.1]octanes". Bioorganic & Medicinal Chemistry Letters. 11 (4): 487–489. doi:10.1016/S0960-894X(00)00701-0. ISSN   0960-894X. PMID   11229754.
  22. Davies, H. M.; Gilliatt, V; Kuhn, L. A.; Saikali, E; Ren, P; Hammond, P. S.; Sexton, T; Childers, S. R. (2001). "Synthesis of 2β-Acyl-3β-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes and Their Binding Affinities at Dopamine and Serotonin Transport Sites". Journal of Medicinal Chemistry. 44 (10): 1509–1515. doi:10.1021/jm000363+. PMID   11334561.
  23. Carroll, F. I.; Gao; Abraham; Lewin; Lew; Patel; Boja; Kuhar (1992). "Probes for the cocaine receptor. Potentially irreversible ligands for the dopamine transporter". Journal of Medicinal Chemistry. 35 (10): 1813–1817. doi:10.1021/jm00088a017. PMID   1588560.
  24. Wu; Reith, M.; Walker, Q.; Kuhn, C.; Carroll, F.; Garris, P. (2002). "Concurrent autoreceptor-mediated control of dopamine release and uptake during neurotransmission: an in vivo voltammetric study". Journal of Neuroscience. 22 (14): 6272–6281. doi:10.1523/JNEUROSCI.22-14-06272.2002. PMC   6757948 . PMID   12122086.
  25. Murthy, V; Martin, TJ; Kim, S; Davies, HM; Childers, SR (August 2008). "In vivo characterization of a novel phenylisothiocyanate tropane analog at monoamine transporters in rat brain". J. Pharmacol. Exp. Ther. 326 (2): 587–95. doi:10.1124/jpet.108.138842. PMID   18492949. S2CID   5996473.
  26. Xu, L.; Kulkarni, S. S.; Izenwasser, S.; Katz, J. L.; Kopajtic, T.; Lomenzo, S. A.; Newman, A. H.; Trudell, M. L. (2004). "Synthesis and Monoamine Transporter Binding of 2-(Diarylmethoxymethyl)-3β-aryltropane Derivatives". Journal of Medicinal Chemistry. 47 (7): 1676–82. doi:10.1021/jm030430a. PMID   15027858.
  27. Hong, W. C.; Kopajtic, T. A.; Xu, L.; Lomenzo, S. A.; Jean, B.; Madura, J. D.; Surratt, C. K.; Trudell, M. L.; Katz, J. L. (2016). "2-Substituted 3 -Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations". Journal of Pharmacology and Experimental Therapeutics. 356 (3): 624–634. doi:10.1124/jpet.115.230722. ISSN   1521-0103. PMC   4767397 . PMID   26769919. nih.gov article (inclu. structural depictions)
  28. Cesati, RR 3rd; Tamagnan, G; Baldwin, RM; Zoghbi, SS; Innis, RB; Kula, NS; Baldessarini, RJ; Katzenellenbogen, JA (2002). "Synthesis of cyclopentadienyltricarbonyl rhenium phenyltropanes by double ligand transfer: organometallic ligands for the dopamine transporter". Bioconjug Chem. 13 (1): 29–39. doi:10.1021/bc010011x. PMID   11792176.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  29. Bloom, Jacob W. G.; Wheeler, Steven E. (2011). "Taking the Aromaticity out of Aromatic Interactions". Angew. Chem. 123 (34): 7993–7995. Bibcode:2011AngCh.123.7993B. doi:10.1002/ange.201102982.
  30. A novel spirocyclic tropanyl-Δ2-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake. Bioorg Med Chem 2012 Nov 10;20(21):6344-55. Epub 2012 Sep 10.
  31. Hanna, Mona M. (2007). "Synthesis of some tropane derivatives of anticipated activity on the reuptake of norepinephrine and/or serotonin". Bioorganic. 15 (24): 7765–7772. doi:10.1016/j.bmc.2007.08.055. PMID   17870537.
  32. Goodman, Mark M. (2003). "Synthesis and Characterization of Iodine-123 Labeled 2β-Carbomethoxy-3β-(4′-((Z)-2-iodoethenyl)phenyl)nortropane. A Ligand for in Vivo Imaging of Serotonin Transporters by Single-Photon-Emission Tomography". Journal of Medicinal Chemistry. 46 (6): 925–935. doi:10.1021/jm0100180. PMID   12620070.
  33. Blough, B.; Abraham, P.; Lewin, A.; Kuhar, M.; Boja, J.; Carroll, F. (1996). "Synthesis and transporter binding properties of 3β-(4′-alkyl-, 4′-alkenyl-, and 4′-alkynylphenyl)nortropane-2β-carboxylic acid methyl esters: serotonin transporter selective analogs". Journal of Medicinal Chemistry . 39 (20): 4027–4035. doi:10.1021/jm960409s. PMID   8831768. S2CID   21616809.
  34. Spealman, R. D.; Kelleher, R. T. (Mar 1981). "Self-administration of cocaine derivatives by squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics. 216 (3): 532–536. ISSN   0022-3565. PMID   7205634.
  35. Carroll, F.; Tyagi, S.; Blough, B.; Kuhar, M.; Navarro, H. (2005). "Synthesis and monoamine transporter binding properties of 3α-(substituted phenyl)nortropane-2β-carboxylic acid methyl esters. Norepinephrine transporter selective compounds". Journal of Medicinal Chemistry . 48 (11): 3852–3857. doi:10.1021/jm058164j. PMID   15916437.
  36. Purushotham, M; Sheri, A; Pham-Huu, D. P.; Madras, B. K.; Janowsky, A; Meltzer, P. C. (2011). "The synthesis and biological evaluation of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8-thiabicyclo3.2.1octanes". Bioorganic & Medicinal Chemistry Letters. 21 (1): 48–51. doi:10.1016/j.bmcl.2010.11.076. PMC   3015105 . PMID   21146984.
  37. 1 2 Wu, Xiaoai; Cai, Huawei; Ge, Ran; Li, Lin; Jia, Zhiyun (2015). "Recent Progress of Imaging Agents for Parkinson's Disease". Current Neuropharmacology. 12 (6): 551–563. doi:10.2174/1570159X13666141204221238. ISSN   1570-159X. PMC   4428027 . PMID   25977680.
  38. U.S. patent 6,150,376
  39. WO 0007994,Kozikowski, Alan P.&Smith, Miles P.,"Novel bi- and tri-cyclic aza compounds and their uses",published 2000-02-17, assigned to Georgetown University
  40. Sakamuri, Sukumar; et al. (2000). "Synthesis of novel spirocyclic cocaine analogs using the Suzuki coupling". Tetrahedron Letters. 41 (13): 2055–2058. doi:10.1016/S0040-4039(00)00113-1.
  41. exo-2-Phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic Acid: A New Constrained Proline Analogue. Source: Tetrahedron Letters, Volume 36, Number 39, 25 September 1995, pp. 7123-7126(4)
  42. Kozikowski, A. P.; Araldi, G. L.; Boja, J.; Meil, W. M.; Johnson, K. M.; Flippen-Anderson, J. L.; George, C.; Saiah, E. (1998). "Chemistry and Pharmacology of the Piperidine-Based Analogues of Cocaine. Identification of Potent DAT Inhibitors Lacking the Tropane Skeleton". Journal of Medicinal Chemistry. 41 (11): 1962–9. CiteSeerX   10.1.1.512.7158 . doi:10.1021/jm980028+. PMID   9599245.
  43. NIH U.S. National Library of Medicine. PubChem CID: 44337825, InChI Key: MHDRABCQAWNSIK-PZORYLMUSA-N
  44. Further SAR Studies of Piperidine-Based Analogues of Cocaine. 2. Potent Dopamine and Serotonin Reuptake Inhibitors J. Med. Chem. 2000,43,1215-1222
  45. Napier, Susan; Bingham, Matilda (2009). Transporters as Targets for Drugs. Topics in Medicinal Chemistry. Vol. 4. Bibcode:2009ttd..book.....N. doi:10.1007/978-3-540-87912-1. ISBN   978-3-540-87911-4.
  46. Stehouwer, Jeffrey S. (2006). "Synthesis, Radiosynthesis, and Biological Evaluation of Carbon-11 Labeled 2β-Carbomethoxy-3β-(3′-(( Z )-2-haloethenyl)phenyl)nortropanes: Candidate Radioligands for in Vivo Imaging of the Serotonin Transporter with Positron Emission Tomography". Journal of Medicinal Chemistry. 49 (23): 6760–6767. doi:10.1021/jm060641q. PMID   17154506.
  47. Deskus, Jeffrey A. (2007). "Conformationally restricted homotryptamines 3. Indole tetrahydropyridines and cyclohexenylamines as selective serotonin reuptake inhibitors". Bioorganic & Medicinal Chemistry. 17 (11): 3099–3104. doi:10.1016/j.bmcl.2007.03.040. PMID   17391962.
  48. Schmitz, William D. (2005). "Homotryptamines as potent and selective serotonin reuptake inhibitors (SSRIs)". Bioorganic & Medicinal Chemistry. 15 (6): 1619–1621. doi:10.1016/j.bmcl.2005.01.059. PMID   15745809.
  49. Plisson, Christophe (2007). "Synthesis and in Vivo Evaluation of Fluorine-18 and Iodine-123 Labeled 2β-Carbo(2-fluoroethoxy)-3β-(4′-(( Z )-2-iodoethenyl)phenyl)nortropane as a Candidate Serotonin Transporter Imaging Agent". Journal of Medicinal Chemistry. 50 (19): 4553–4560. doi:10.1021/jm061303s. PMID   17705359.
  50. McMahon, C. G.; McMahon, C. N.; Leow, L. J. (2006). "New agents in the treatment of premature ejaculation". Neuropsychiatric Disease and Treatment. 2 (4): 489–503. doi: 10.2147/nedt.2006.2.4.489 . PMC   2671940 . PMID   19412497.
  51. Leung, K (2004). "N-4-Fluorobut-2-yn-1-yl-2β-carbo-[11C]methoxy-3β-phenyltropane". PMID   22073420.{{cite journal}}: Cite journal requires |journal= (help)
  52. Stenzinger, W; Blömker, A; Hiddemann, W; de Loo, J (1990). "Treatment of refractory multiple myeloma with the vincristine-adriamycin-dexamethasone (VAD) regimen". Blut. 61 (2–3): 55–9. doi:10.1007/bf02076700. PMID   2207342. S2CID   25860357.
  53. Ma, S; Cheng, MH; Guthrie, DA; Newman, AH; Bahar, I; Sorkin, A (2017). "Targeting of dopamine transporter to filopodia requires an outward-facing conformation of the transporter". Sci Rep. 7 (1): 5399. Bibcode:2017NatSR...7.5399M. doi:10.1038/s41598-017-05637-x. PMC   5511133 . PMID   28710426.

Im-pact indices (exact locations within sources cited) & foot-notations

  1. [1] Page #929 (5th page of article) § II
  2. Many of the RTI phenyltropanes are "RTI-4229-×××" where × is the specific phenyltropane code number.

    e.g.RTI-55 is in-fact RTI-4229-55 but given below as simply RTI-55 for the sake of simplicity in shorthand (following as is done in the literature itself) as the subject matter in context is wholly within the scope of the phenyltropane coded category herein. Sometimes (more rarely) it is given as RTI-COC-××× for "cocaine derivative."

    Worth mentioning in notation as to explain that other compounds entirely unrelated can be found with the same "RTI-×××" short-numbered assignation. Therefore it is to be expected that within different contexts a compound or chemical of the same name very possibly could be in reference to a entirely other substance of another chemical series non-analogous to those in this topic.
  3. [1] Page #970 (46th page of article) §B, 10th line
  4. [1] Page #971 (47th page of article) 1st ¶, 10th line
  5. Beta (i.e. 2,3 Rectus)-Carbmethoxy-Phenyl-Tropane
  6. Beta (i.e. 2,3 Rectus)-Carbmethoxy-Fluorophenyl-Tropane
  7. [1] Page #940 (16th page of article) underneath Table 8., above § 4
  8. [1] Page #941 (17th page of article) Figure 10
  9. [1] Page #967 (43rd page of article) 2nd column
  10. [1] Page #967 (43rd page of article) 2nd column
  11. [1] Page #955 (31st page of article) 1st (left) column, 2nd ¶