This is a list of methylphenidate (MPH or MPD) analogues, or Phenidates. The most well known compound from this family, methylphenidate, is widely prescribed around the world for the treatment of attention deficit hyperactivity disorder (ADHD) and certain other indications. Several other derivatives including rimiterol, phacetoperane and pipradrol also have more limited medical application. A rather larger number of these compounds have been sold in recent years as designer drugs, either as quasi-legal substitutes for illicit stimulants such as methamphetamine or cocaine, or as purported "study drugs" or nootropics. [1] [2] [3]
More structurally diverse compounds such as desoxypipradrol (and thus pipradrol, including such derivatives as AL-1095, diphemethoxidine, SCH-5472 and D2PM), and even mefloquine, 2-benzylpiperidine, rimiterol, enpiroline and DMBMPP, can also be considered structurally related, with the former ones also functionally so, as loosely analogous compounds. The acyl group has sometimes been replaced with similar length ketones to increase duration. Alternatively, the methoxycarbonyl has in some cases been replaced with an alkyl group. [4] [5]
Dozens more phenidates and related compounds are known from the academic and patent literature, and molecular modelling and receptor binding studies have established that the aryl and acyl substituents in the phenidate series are functionally identical to the aryl and acyl groups in the phenyltropane series of drugs, suggesting that the central core of these molecules is primarily acting merely as a scaffold to correctly orientate the binding groups, and for each of the hundreds of phenyltropanes that are known, there may be a phenidate equivalent with a comparable activity profile. Albeit with the respective difference in their entropy of binding: cocaine being −5.6 kcal/mol and methylphenidate being −25.5 kcal/mol (Δ s°, measured using [3H]GBR 1278 @ 25 °C). [lower-alpha 1]
Structure | Common name | Chemical name | CAS number | R1 | R2 |
---|---|---|---|---|---|
2-BZPD | 2-Benzylpiperidine | 32838-55-4 | phenyl | H | |
Ritalinic acid | Phenyl(piperidin-2-yl)acetic acid | 19395-41-6 | phenyl | COOH | |
Ritalinamide | 2-Phenyl-2-(piperidin-2-yl)acetamide | 19395-39-2 | phenyl | CONH2 | |
Methylphenidate (MPH) | Methyl phenyl(piperidin-2-yl)acetate | 113-45-1 | phenyl | COOMe | |
Phacetoperane (Lidépran) | [(R)-phenyl-[(2R)-piperidin-2-yl]methyl] acetate | 24558-01-8 | phenyl | OCOMe | |
Rimiterol | 4-{(S)-hydroxy[(2R)-piperidin-2-yl]methyl}benzene-1,2-diol | 32953-89-2 | 3,4-dihydroxyphenyl | hydroxy | |
Ethylphenidate (EPH) | Ethyl phenyl(piperidin-2-yl)acetate | 57413-43-1 | phenyl | COOEt | |
Propylphenidate (PPH) | Propyl phenyl(piperidin-2-yl)acetate | 1071564-47-0 | phenyl | COOnPr | |
Isopropylphenidate (IPH) | Propan-2-yl 2-phenyl-2-(piperidin-2-yl)acetate | 93148-46-0 | phenyl | COOiPr | |
Butylphenidate (BPH) | Butyl phenyl(piperidin-2-yl)acetate | phenyl | COOnBu | ||
3-Chloromethylphenidate (3-Cl-MPH) | Methyl 2-(3-chlorophenyl)-2-(piperidin-2-yl)acetate | 191790-73-5 | 3-chlorophenyl | COOMe | |
3-Bromomethylphenidate (3-Br-MPH) | Methyl 2-(3-bromophenyl)-2-(piperidin-2-yl)acetate | 3-bromophenyl | COOMe | ||
3-Methylmethylphenidate (3-Me-MPH) | Methyl 2-(3-methylphenyl)-2-(piperidin-2-yl)acetate | 3-methylphenyl | COOMe | ||
4-Fluoromethylphenidate (4F-MPH) | Methyl 2-(4-fluorophenyl)-2-(piperidin-2-yl)acetate | 1354631-33-6 | 4-fluorophenyl | COOMe | |
4-Fluoroethylphenidate (4F-EPH) | Ethyl 2-(4-fluorophenyl)-2-(piperidin-2-yl)acetate | 2160555-59-7 | 4-fluorophenyl | COOEt | |
4-Fluoroisopropylphenidate (4F-IPH) | Propan-2-yl 2-(4-fluorophenyl)-2-(piperidin-2-yl)acetate | 4-fluorophenyl | COOiPr | ||
4-Chloromethylphenidate (4-Cl-MPH) | Methyl 2-(4-chlorophenyl)-2-(piperidin-2-yl)acetate | 680996-44-5 | 4-chlorophenyl | COOMe | |
3,4-Dichloromethylphenidate (3,4-DCMP) | Methyl 2-(3,4-dichlorophenyl)-2-(piperidin-2-yl)acetate | 1400742-68-8 | 3,4-dichlorophenyl | COOMe | |
3,4-Dichloroethylphenidate (3,4-DCEP) | Ethyl 2-(3,4-dichlorophenyl)-2-(piperidin-2-yl)acetate | 3,4-dichlorophenyl | COOEt | ||
4-Bromomethylphenidate (4-Br-MPH) | Methyl 2-(4-bromophenyl)-2-(piperidin-2-yl)acetate | 203056-13-7 | 4-bromophenyl | COOMe | |
4-Bromoethylphenidate (4-Br-EPH) | Ethyl 2-(4-bromophenyl)-2-(piperidin-2-yl)acetate | 1391486-43-3 | 4-bromophenyl | COOEt | |
4-Methylmethylphenidate (4-Me-MPH) | Methyl 2-(4-methylphenyl)-2-(piperidin-2-yl)acetate | 191790-79-1 | 4-methylphenyl | COOMe | |
4-Methylisopropylphenidate (4-Me-IPH) | Propan-2-yl 2-(4-methylphenyl)-2-(piperidin-2-yl)acetate | 4-methylphenyl | COOiPr | ||
4-Nitromethylphenidate (4-NO2-MPH) | Methyl 2-(4-nitrophenyl)-2-(piperidin-2-yl)acetate | 4-nitrophenyl | COOMe | ||
Methylenedioxymethylphenidate (MDMPH) | Methyl (1,3-benzodioxol-5-yl)(piperidin-2-yl)acetate | 3,4-methylenedioxyphenyl | COOMe | ||
Methylnaphthidate (HDMP-28) | Methyl (naphthalen-2-yl)(piperidin-2-yl)acetate | 231299-82-4 | naphthalen-2-yl | COOMe | |
Ethylnaphthidate (HDEP-28) | Ethyl (naphthalen-2-yl)(piperidin-2-yl)acetate | 2170529-69-6 | naphthalen-2-yl | COOEt | |
Isopropylnaphthidate | Propan-2-yl (naphthalen-2-yl)(piperidin-2-yl)acetate | naphthalen-2-yl | COOiPr | ||
MTMP | Methyl (thiophen-2-yl)(piperidin-2-yl)acetate | thiophen-2-yl | COOMe | ||
α-acetyl-2-benzylpiperidine | 1-Phenyl-1-(piperidin-2-yl)propan-2-one | phenyl | acetyl | ||
CPMBP | 2-[1-(3-chlorophenyl)-3-methylbutyl]piperidine | 3-chlorophenyl | isobutyl | ||
Desoxypipradrol (2-DPMP) | 2-benzhydrylpiperidine | 519-74-4 | phenyl | phenyl | |
Pipradrol (Meratran) | Diphenyl(piperidin-2-yl)methanol | 467-60-7 | phenyl | hydroxy,phenyl |
A number of related compounds are known which fit the same general structural pattern, but with substitution on the piperidine ring (e.g. SCH-5472, Difemetorex, N-benzylethylphenidate), or the piperidine ring replaced by other heterocycles such as pyrrolidine (e.g. diphenylprolinol, 2-Diphenylmethylpyrrolidine), morpholine (e.g. Methylmorphenate, 3-Benzhydrylmorpholine) or quinoline (e.g. AL-1095, Butyltolylquinuclidine).
Structure | Common name | Chemical name | CAS number |
---|---|---|---|
SCH-5472 | 2-benzhydryl-1-methyl-piperidin-3-ol | 20068-90-0 | |
Difemetorex | 2-[2-(diphenylmethyl)piperidin-1-yl]ethanol | 13862-07-2 | |
N-benzylethylphenidate | Ethyl (1-benzylpiperidin-2-yl)(phenyl)acetate | ||
Serdexmethylphenidate | (1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium-3-carbonyl)-L-serinate chloride | 1996626-30-2 | |
DMBMPP | 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine | 1391499-52-7 | |
Diphenylprolinol (D2PM) | diphenyl(pyrrolidin-2-yl)methanol | 22348-32-9 | |
2-Benzhydrylpyrrolidine | 2-(Diphenylmethyl)pyrrolidine | 119237-64-8 | |
HDMP-29 | Methyl (naphthalen-2-yl)(pyrrolidin-2-yl)acetate | ||
Methylmorphenate | Methyl morpholin-3-yl(phenyl)acetate | ||
3-Benzhydrylmorpholine | 3-(diphenylmethyl)morpholine | 93406-27-0 | |
AL-1095 | 2-(1-phenyl-1-(p-chlorophenyl)methyl)-3-hydroxyquinuclidine | 54549-19-8 | |
Butyltolylquinuclidine | (2R,3S,4S)-2-butyl-3-p-tolylquinuclidine |
Methylphenidate (and its derivatives) have two chiral centers, meaning that it, and each of its analogues, have four possible enantiomers, each with differing pharmacokinetics and receptor binding profiles. In practice methylphenidate is most commonly used as pairs of diastereomers rather than isolated single enantiomers or a mixture of all four isomers. Forms include the racemate, the enantiopure (dextro or levo) of its stereoisomers; erythro or threo (either + or -) among its diastereoisomers, the chiral isomers S,S; S,R/R,S or R,R and, lastly, the isomeric conformers (which are not absolute) of either its anti- or gauche- rotamer. The variant with optimized efficacy is not the usually attested generic or common pharmaceutical brands (e.g. Ritalin, Daytrana etc.) but the (R,R)-dextro-(+)-threo-anti (sold as Focalin), which has a binding profile on par with or better than that of cocaine. [lower-alpha 2] (Note however the measure of fivefold (5×) discrepancy in the entropy of binding at their presumed shared target binding site, which may account for the higher abuse potential of cocaine over methylphenidate despite affinity for associating; i.e the latter dissociates more readily once bound despite efficacy for binding. [lower-alpha 3] ) Furthermore, the energy to change between its two rotamers involves the stabilizing of the hydrogen bond between the protonated amine (of an 8.5 pKa) with the ester carbonyl resulting in reduced instances of "gauche—gauche" interactions via its favoring for activity the "anti"-conformer for putative homergic-psychostimulating pharmacokinetic properties, postulating that one inherent conformational isomer ("anti") is necessitated for the activity of the threo diastereoisomer. [lower-alpha 4]
Also of note is that methylphenidate in demethylated form is acidic; a metabolite (and precursor) known as ritalinic acid. [8] This gives the potential to yield a conjugate salt [9] form effectively protonated by a salt nearly chemically duplicate/identical to its own structure; creating a "methylphenidate ritalinate". [10]
Compound | S. Singh's alphanumeric assignation (name) | R1 | R2 | IC50 (nM) (Inhibition of [3H]WIN 35428 binding) | IC50 (nM) (Inhibition of [3H]DA uptake) | Selectivity uptake/binding |
---|---|---|---|---|---|---|
(D-threo-methylphenidate) | H, H | 33 | 244 ± 142 (171 ± 10) | 7.4 | ||
(L-threo-methylphenidate) | 540 | 5100 (1468 ± 112) | 9.4 | |||
(D/L-threo-methylphenidate) "eudismic ratio" | 6.4 | 20.9 (8.6) | - | |||
(DL-threo-methylphenidate) | 83.0 ± 7.9 | 224 ± 19 | 2.7 | |||
(R-benzoyl-methylecgonine) (cocaine) | (H, H) | 173 ± 13 | 404 ± 26 | 2.3 | ||
351a (4F-MPH) | F | H y d r o g e n i.e. H | 35.0 ± 3.0 | 142 ± 2.0 | 4.1 | |
351b | Cl | 20.6 ± 3.4 | 73.8 ± 8.1 | 3.6 | ||
351c | Br | 6.9 ± 0.1 | 26.3 ± 5.8 | 3.8 | ||
351d | (d) Br | - | 22.5 ± 2.1 | - | ||
351e | (l) Br | - | 408 ± 17 | - | ||
351d/e "eudismic ratio" | (d/l) Br | - | 18.1 | - | ||
351f | I | 14.0 ± 0.1 | 64.5 ± 3.5 | 4.6 | ||
351g | OH | 98.0 ± 10 | 340 ± 70 | 3.5 | ||
351h | OCH3 | 83 ± 11 | 293 ± 48 | 3.5 | ||
351i | (d) OCH3 | - | 205 ± 10 | - | ||
351j | (l) OCH3 | - | 3588 ± 310 | - | ||
351i/j "eudismic ratio" | (d/l) OCH3 | - | 17.5 | - | ||
351k (4-Me-MPH) | CH3 | 33.0 ± 1.2 | 126 ± 1 | 3.8 | ||
351l | t-Bu | 13500 ± 450 | 9350 ± 950 | 0.7 | ||
351m | NH2.HCl | 34.6 ± 4.0 | 115 ± 10 | 3.3 | ||
351n | NO2 | 494 ± 33 | 1610 ± 210 | 3.3 | ||
352a | F | 40.5 ± 4.5 | 160 ± 0.00 | 4.0 | ||
352b | Cl | 5.1 ± 1.6 | 23.0 ± 3.0 | 4.5 | ||
352c | Br | 4.2 ± 0.2 | 12.8 ± 0.20 | 3.1 | ||
352d | OH | 321 ± 1.0 | 790 ± 30 | 2.5 | ||
352e | OMe | 288 ± 53 | 635 ± 35 | 0.2 | ||
352f | Me | 21.4 ± 1.1 | 100 ± 18 | 4.7 | ||
352g | NH2.HCl | 265 ± 5 | 578 ± 160 | 2.2 | ||
353a | 2′-F | 1420 ± 120 | 2900 ± 300 | 2.1 | ||
353b | 2′-Cl | 1950 ± 230 | 2660 ± 140 | 1.4 | ||
353c | 2′-Br | 1870 ± 135 | 3410 ± 290 | 1.8 | ||
353d | 2′-OH | 23100 ± 50 | 35,800 ± 800 | 1.6 | ||
353e | 2′-OCH3 | 101,000 ± 10,000 | 81,000 ± 2000 | 0.8 | ||
354a (3,4-DCMP) | Cl, Cl (3′,4′-Cl2) | 5.3 ± 0.7 | 7.0 ± 0.6 | 1.3 | ||
354b | I | OH | 42 ± 21 | 195 ± 197 | 4.6 | |
354c | OMe, OMe (3′,4′-OMe2) | 810 ± 10 | 1760 ± 160 | 2.2 |
Both analogues 374 & 375 displayed higher potency than methylphenidate at DAT. In further comparison, 375 (the 2-naphthyl) was additionally two & a half times more potent than 374 (the 1-naphthyl isomer). [lower-alpha 6]
Compound | S. Singh's alphanumeric assignation (name) | Ring | Ki (nM) (Inhibition of [125I]IPT binding) | Ki (nM) (Inhibition of [3H]DA uptake) | Selectivity uptake/binding |
---|---|---|---|---|---|
(D-threo-methylphenidate) | benzene | 324 | - | - | |
(DL-threo-methylphenidate) | 82 ± 77 | 429 ± 88 | 0.7 | ||
374 | 1-naphthalene | 194 ± 15 | 1981 ± 443 | 10.2 | |
375 (HDMP-28) | 2-naphthalene | 79.5 | 85.2 ± 25 | 1.0 | |
376 | benzyl | >5000 | - | - |
Compound | S. Singh's alphanumeric assignation (name) | R | IC50 (nM) (Inhibition of binding at DAT) |
---|---|---|---|
373a | H | 500 ± 25 | |
373b | 4″-OH | 1220 ± 140 | |
373c | 4″-CH3 | 139 ± 13 | |
373d | 3″-Cl | 161 ± 18 | |
373e | 3″-Me | 108 ± 16 |
Compound | S. Singh's alphanumeric assignation (name) | Cycloalkane ring | Ki (nM) (Inhibition of binding) |
---|---|---|---|
380 | 2-pyrrolidine (cyclopentane) | 1336 ± 108 | |
381 | 2-azepane (cycloheptane) | 1765 ± 113 | |
382 | 2-azocane (cyclooctane) | 3321 ± 551 | |
383 | 4-1,3-oxazinane (cyclohexane) | 6689 ± 1348 |
Methyl 2-(1,2-oxazinan-3-yl)-2-phenylacetate |
Methyl 2-(1,3-oxazinan-2-yl)-2-phenylacetate |
☝The two other (in addition to compound 383) potential oxazinane methylphenidate analogues. |
Methyl 2-phenyl-2-(morpholin-3-yl)acetate A.K.A. Methyl 2-morpholin-3-yl-2-phenylacetate | ☜ Methylmorphenate methylphenidate analogue. [12] |
Structures of Azido-iodo-N-benzyl analogues of methylphenidate with affinities. [13]
Structure | Compound | R1 | R2 | Ki (nM) (Inhibition of [3H]WIN 35428 binding) | IC50 (nM) (Inhibition of [3H]DA uptake) |
---|---|---|---|---|---|
(±)—threo-methylphenidate | H | H | 25 ± 1 | 156 ± 58 | |
(±)—4-I-methylphenidate | para-iodo | H | 14 ± 3ɑ | 11 ± 2b | |
(±)—3-I-methylphenidate | meta-iodo | H | 4.5 ± 1ɑ | 14 ± 5b | |
(±)—p-N3-N-Bn-4-I-methylphenidate | para-iodo | para-N3-N-Benzyl | 363 ± 28ɑ | 2764 ± 196bc | |
(±)—m-N3-N-Bn-4-I-methylphenidate | para-iodo | meta-N3-N-Benzyl | 2754 ± 169ɑ | 7966 ± 348bc | |
(±)—o-N3-N-Bn-4-I-methylphenidate | para-iodo | ortho-N3-N-Benzyl | 517 ± 65ɑ | 1232 ± 70bc | |
(±)—p-N3-N-Bn-3-I-methylphenidate | meta-iodo | para-N3-N-Benzyl | 658 ± 70ɑ | 1828 ± 261bc | |
(±)—m-N3-N-Bn-3-I-methylphenidate | meta-iodo | meta-N3-N-Benzyl | 2056 ± 73ɑ | 4627 ± 238bc | |
(±)—o-N3-N-Bn-3-I-methylphenidate | meta-iodo | ortho-N3-N-Benzyl | 1112 ± 163ɑ | 2696 ± 178bc | |
(±)—N-Bn-methylphenidate | H | N-Benzyl | — | — | |
(±)—N-Bn-3-chloro-methylphenidate | 3-Cl | N-Benzyl | — | — | |
(±)—N-Bn-3,4-dichloro-methylphenidate | 3,4-diCl | N-Benzyl | — | — | |
(±)—p-chloro-N-Bn-methylphenidate | H | para-Cl-N-Benzyl | — | — | |
(±)—p-methoxy-N-Bn-methylphenidate | H | para-OMe-N-Benzyl | — | — | |
(±)—m-chloro-N-Bn-methylphenidate | H | meta-Cl-N-Benzyl | — | — | |
(±)—p-nitro-N-Bn-methylphenidate | H | para-NO2-N-Benzyl | — | — |
Structure | R1 | R2 | R3 | Dopamine transporter Ki (nM) (Inhibition of [I125H]RTI-55 binding) | DA uptake IC50 (nM) | Serotonin transporter Ki (nM) (Inhibition of [I125H]RTI-55 binding) | 5HT uptake IC50 (nM) | Norepinephrine transporter Ki (nM) (Inhibition of [I125H]RTI-55 binding) | NE uptake IC50 (nM) | NE/DA selectivity (binding displacement) | NE/DA selectivity (uptake blocking) |
---|---|---|---|---|---|---|---|---|---|---|---|
Cocaine | — ɑ | — b | — c | 500 ± 65 | 240 ± 15 | 340 ± 40 | 250 ± 40 | 500 ± 90 | 210 ± 30 | 1.0 | 0.88 |
H | COOCH3 | H | 110 ± 9 | 79 ± 16 | 65,000 ± 4,000 | 5,100 ± 7,000 | 660 ± 50 | 61 ± 14 | 6.0 | 0.77 | |
4-chloro | COOCH3 | H | 25 ± 8 2,000 ± 600 | 11 ± 28 2,700 ± 1,000 | 6,000 ± 100 5,900 ± 200 | >9,800 >10 mM | 110 ± 40 >6,100 | 11 ± 3 1,400 ± 400 | 4.4 | 1.0 | |
4-chloro | methyl | H | 180 ± 70 >3,900 | 22 ± 7 1,500 ± 700 | 4,900 ± 500 >9,100 | 1,900 ± 300 4,700 ± 800 | 360 ± 140 >6,300 | 35 ± 13 3,200 ± 800 | 2.0 | 1.6 | |
4-chloro | ethyl | H | 37 ± 10 1,800 ± 300 | 23 ± 5 2,800 ± 700 | 7,800 ± 800 4,200 ± 400 | 2,400 ± 400 4,100 ± 1,000 | 360 ± 60 >9,200 | 210 ± 30 1,300 ± 400 | 9.7 | 9.1 | |
4-chloro | propyl | H | 11 ± 3 380 ± 40 | 7.4 ± 0.4 450 ± 60 | 2,700 ± 600 3,200 ± 1,100 | 2,900 ± 1,100 1,300 ± 7 | 200 ± 80 1,400 ± 400 | 50 ± 15 200 ± 50 | 18.0 | 6.8 | |
4-chloro | isopropyl | H | 46 ± 16 900 ± 320 | 32 ± 6 990 ± 280 | 5,300 ± 1,300 >10 mM | 3,300 ± 400 — | 810 ± 170 >10 mM | 51 ± 20 — | 18.0 | 1.6 | |
4-chloro | butyl | H | 7.8 ± 1.1 290 ± 70 | 8.2 ± 2.1 170 ± 40 | 4,300 ± 400 4,800 ± 700 | 4,000 ± 400 3,300 ± 600 | 230 ± 30 1,600 ± 300 | 26 ± 7 180 ± 60 | 29.0 | 3.2 | |
4-chloro | isobutyl | H | 16 ± 4 170 ± 50 | 8.6 ± 2.9 380 ± 130 | 5,900 ± 900 4,300 ± 500 | 490 ± 80 540 ± 150 | 840 ± 130 4,500 ± 1,500 | 120 ± 40 750 ± 170 | 53.0 | 14.0 | |
4-chloro | pentyl | H | 23 ± 7 870 ± 140 | 45 ± 14 650 ± 20 | 2,200 ± 100 3,600 ± 1,000 | 1,500 ± 300 1,700 ± 700 | 160 ± 40 1,500 ± 300 | 49 ± 16 860 ± 330 | 7.0 | 1.1 | |
4-chloro | isopentyl | H | 3.6 ± 1.2 510 ± 170 | 14 ± 2 680 ± 120 | 5,000 ± 470 6,700 ± 500 | 7,300 ± 1,400 >8,300 | 830 ± 110 12,000 ± 1,400 | 210 ± 40 3,000 ± 540 | 230.0 | 15.0 | |
4-chloro | neopentyl | H | 120 ± 40 600 ± 40 | 60 ± 2 670 ± 260 | 3,900 ± 500 3,500 ± 1,000 | >8,300 1,800 ± 600 | 1,400 ± 400 >5,500 | 520 ± 110 730 ± 250 | 12.0 | 8.7 | |
4-chloro | cyclopentylmethyl | H | 9.4 ± 1.5 310 ± 80 | 21 ± 1 180 ± 20 | 2,900 ± 80 3,200 ± 700 | 2,100 ± 900 5,600 ± 1,400 | 1,700 ± 600 2,600 ± 800 | 310 ± 40 730 ± 230 | 180.0 | 15.0 | |
4-chloro | cyclohexylmethyl | H | 130 ± 40 260 ± 30 | 230 ± 70 410 ± 60 | 900 ± 400 3,700 ± 500 | 1,000 ± 200 6,400 ± 1,300 | 4,200 ± 200 4,300 ± 200 | 940 ± 140 1,700 ± 600 | 32.0 | 4.1 | |
4-chloro | benzyl | H | 440 ± 110 550 ± 60 | 370 ± 90 390 ± 60 | 1,100 ± 200 4,300 ± 800 | 1,100 ± 200 4,700 ± 500 | 2,900 ± 800 4,000 ± 800 | 2,900 ± 600 >8,800 | 6.6 | 7.8 | |
4-chloro | phenethyl | H | 24 ± 9 700 ± 90 | 160 ± 20 420 ± 140 | 640 ± 60 1,800 ± 70 | 650 ± 210 210 ± 900d | 1,800 ± 600 2,400 ± 700 | 680 ± 240 610 ± 150 | 75.0 | 4.3 | |
4-chloro | phenpropyl | H | 440 ± 150 2,900 ± 900 | 290 ± 90 1,400 ± 400 | 700 ± 200 1,500 ± 200 | 1,600 ± 300 1,200 ± 400 | 490 ± 100 1,500 ± 200 | 600 ± 140 1,700 ± 200 | 1.1 | 2.1 | |
4-chloro | 3-pentyl | H | 400 ± 80 >5,700 | 240 ± 60 1,200 ± 90 | 3,900 ± 300 4,800 ± 1,100 | >9,400 >9,600 | 970 ± 290 4,300 ± 200 | 330 ± 80 3,800 ± 30 | 2.4 | 1.4 | |
4-chloro | cyclopentyl | H | 36 ± 10 690 ± 140 | 27 ± 8.3 240 ± 30 | 5,700 ± 1,100 4,600 ± 700 | 4,600 ± 800 4,200 ± 900 | 380 ± 120 3,300 ± 800 | 44 ± 18 1,000 ± 300 | 11.0 | 1.6 | |
3-chloro | isobutyl | H | 3.7 ± 1.1 140 ± 30 | 2.8 ± 0.4 88 ± 12 | 3,200 ± 400 3,200 ± 400 | 2,100 ± 100 870 ± 230 | 23 ± 6 340 ± 50 | 14 ± 1 73 ± 5 | 6.2 | 5.0 | |
3,4-dichloro | COOCH3 | H | 1.4 ± 0.1 90 ± 14 | 23 ± 3 800 ± 110 | 1,600 ± 150 2,500 ± 420 | 540 ± 110 1,100 ± 90 | 14 ± 6 4,200 ± 1,900 | 10 ± 1 190 ± 50 | 10.0 | 0.43 | |
3,4-dichloro | propyl | H | 0.97 ± 0.31 43 ± 9 | 4.5 ± 0.4 88 ± 32 | 1,800 ± 500 450 ± 80 | 560 ± 120 180 ± 60 | 3.9 ± 1.4 30 ± 8 | 8.1 ± 3.8 47 ± 22 | 4.0 | 1.8 | |
3,4-dichloro | butyl | H | 2.3 ± 0.2 29 ± 5 | 5.7 ± 0.5 67 ± 13 | 1,300 ± 300 1,100 ± 200 | 1,400 ± 300 550 ± 80 | 12 ± 3 31 ± 11 | 27 ± 10 63 ± 27 | 5.2 | 4.7 | |
3,4-dichloro | isobutyl | H | 1.0 ± 0.5 31 ± 11 | 5.5 ± 1.3 13 ± 3 | 1,600 ± 100 450 ± 40 | 1,100 ± 300 290 ± 60 | 25 ± 9 120 ± 30 | 9.0 ± 1.2 19 ± 3 | 25.0 | 1.6 | |
3,4-dichloro | isobutyl | CH3 | 6.6 ± 0.9 44 ± 12 | 13 ± 4 45 ± 4 | 1,300 ± 200 1,500 ± 300 | 1,400 ± 500 2,400 ± 700 | 190 ± 60 660 ± 130 | 28 ± 3 100 ± 19 | 29.0 | 2.2 | |
4-methoxy | isobutyl | H | 52 ± 16 770 ± 220 | 25 ± 9 400 ± 120 | 2,800 ± 600 950 ± 190 | 3,500 ± 500 1,200 ± 300 | 3,100 ± 200 16,000 ± 2,000 | 410 ± 90 1,600 ± 400 | 60.0 | 16.0 | |
3-methoxy | isobutyl | H | 22 ± 5 950 ± 190 | 35 ± 12 140 ± 20 | 4,200 ± 400 3,800 ± 600 | 2,700 ± 800 2,600 ± 300 | 3,800 ± 500 12,000 ± 2,300 | 330 ± 40 1,400 ± 90 | 170.0 | 9.4 | |
4-isopropyl | isobutyl | H | 3,300 ± 600 >6,500 | 4,000 ± 400 >9,100 | 3,300 ± 600 1,700 ± 500 | 4,700 ± 700 1,700 ± 100 | 2,500 ± 600 3,200 ± 600 | 7,100 ± 1,800 >8,700 | 0.76 | 1.8 | |
H | COCH3 | H | 370 ± 70 | 190 ± 50 | 7,800 ± 1,200 | >9,700 | 2,700 ± 400 | 220 ± 30 | 7.3 | 1.2 |
Two of the compounds tested, the weakest two @ DAT & second to the final two on the table below, were designed to elucidate the necessity of both constrained rings in the efficacy of the below series of compounds at binding by removing one or the other of the two rings in their entirety. The first of the two retain the original piperidine ring had with methylphenidate but has the constrained B ring that is common to the restricted rotational analogues thereof removed. The one below lacks the piperdine ring native to methylphenidate but keeps the ring that hindered the flexibility of the original MPH conformation. Though their potency at binding is weak in comparison to the series, with the potency shared being approximately equal between the two; the latter compound (the one more nearly resembling the substrate class of dopaminergic releasing agents similar to phenmetrazine) is 8.3-fold more potent @ DA uptake.
Compoundɑ | R & X substitution(s) | Ki (nM) @ DAT with [33]WIN 35,065-2 | nH @ DAT with [33]WIN 35,065-2 | Ki (nM) or % inhibition @ NET with [33]Nisoxetine | nH @ NET with [33]Nisoxetine | Ki (nM) or % inhibition @ 5-HTT with [33]Citalopram | nH @ 5-HTT with [33]Citalopram | [33]DA uptake IC50 (nM) | Selectivity [33]Citalopram / [33]WIN 35,065-2 | Selectivity [33]Nisoxetine / [33]WIN 35,065-2 | Selectivity [33]Citalopram / [33]Nisoxetine |
---|---|---|---|---|---|---|---|---|---|---|---|
Cocaine | — | 156 ± 11 | 1.03 ± 0.01 | 1,930 ± 360 | 0.82 ± 0.05 | 306 ± 13 | 1.12 ± 0.15 | 404 ± 26 | 2.0 | 12 | 0.16 |
Methylphenidate | — | 74.6 ± 7.4 | 0.96 ± 0.08 | 270 ± 23 | 0.76 ± 0.06 | 14 ± 8%f | — | 230 ± 16 | >130 | 3.6 | >47 |
3′,4′-dichloro-MPH | — | 4.76 ± 0.62 | 2.07 ± 0.05 | NDh | — | 667 ± 83 | 1.07 ± 0.04 | 7.00 ± 140 | 140 | — | — |
— | 6,610 ± 440 | 0.91 ± 0.01 | 11%b | — | 3,550 ± 70 | 1.79 ± 0.55 | 8,490 ± 1,800 | 0.54 | >0.76 | <0.7 | |
H | 76.2 ± 3.4 | 1.05 ± 0.05 | 138 ± 9.0 | 1.12 ± 0.20 | 5,140 ± 670 | 1.29 ± 0.40 | 244 ± 2.5 | 67 | 1.8 | 37 | |
3′,4′-diCl | 3.39 ± 0.77 | 1.25 ± 0.29 | 28.4 ± 2.5 | 1.56 ± 0.80 | 121 ± 17 | 1.16 ± 0.31 | 11.0 ± 0.00 | 36 | 8.4 | 4.3 | |
2′-Cl | 480 ± 46 | 1.00 ± 0.09 | 2,750; 58%b | 0.96 | 1,840 ± 70 | 1.18 ± 0.06 | 1,260 ± 290 | 3.8 | 5.7 | 0.67 | |
— | 34.6 ± 7.6 | 0.95 ± 0.18 | 160 ± 18 | 1.28 ± 0.12 | 102 ± 8.2 | 1.01 ± 0.02 | 87.6 ± 0.35 | 3.0 | 4.6 | 0.64 | |
CH2OH | 2,100 ± 697 | 0.87 ± 0.09 | NDh | — | 16.2 ± 0.05%f | — | 10,400 ± 530 | >4.8 | — | — | |
CH3 | 7,610 ± 800 | 1.02 ± 0.03 | 8.3%b | — | 11 ± 5%f | — | 7,960 ± 290 | >1.3 | ≫0.66 | — | |
d R=OCH3, X=H | 570 ± 49 | 0.94 ± 0.10 | 2,040; 64 ± 1.7%f | 0.73 | 14 ± 3%f | — | 1,850 ± 160 | >18 | 3.6 | >4.9 | |
R=OH, X=H | 6,250 ± 280 | 0.86 ± 0.03 | 23.7 ± 4.1%b | — | 1 ± 1%f | — | 10,700 ± 750 | ≫1.6 | >0.80 | — | |
R=OH, X=3′,4′-diCl | 35.7 ± 3.2 | 1.00 ± 0.09 | 367 ± 42 | 1.74 ± 0.87 | 2,050 ± 110 | 1.15 ± 0.12 | NDh | 57 | 10 | 5.6 | |
H | 908 ± 160 | 0.88 ± 0.05 | 4030; 52%b | 1.04 | 5 ± 1%f | — | 12,400 ± 1,500 | ≫11 | 4.4 | ≫2.5 | |
3′,4′-diCl | 14.0 ± 1.2 | 1.27 ± 0.20 | 280 ± 76 | 0.68 ± 0.09 | 54 ± 2%f | — | NDh | ~710 | 20 | ~36 | |
R=OH, X=H | 108 ± 7.0 | 0.89 ± 0.10 | 351 ± 85 | 0.94 ± 0.27 | 12 ± 2%f | — | 680 ± 52 | >93 | 3.3 | >28 | |
R=OH, X=3′,4′-diCl | 2.46 ± 0.52 | 1.39 ± 0.20 | 27.9 ± 3.5 | 0.70 ± 0.01 | 168 | 1.02 | NDh | 68 | 11 | 6.0 | |
R=OCH3, X=H | 10.8 ± 0.8 | 0.97 ± 0.07 | 63.7 ± 2.8 | 0.84 ± 0.04 | 2,070; 73 ± 5%f | 0.90 | 61.0 ± 9.3 | 190 | 5.9 | 32 | |
R1=CH3, R2=H | 178 ± 28 | 1.23 ± 0.09 | 694 ± 65 | 0.88 ± 0.13 | 427 | 1.39 | 368 | 2.4 | 3.9 | 0.62 | |
R1=H, R2=CH3 | 119 ± 20 | 1.17 ± 0.12 | 76.0 ± 12 | 0.88 ± 0.06 | 243 | 1.17 | 248 | 2.0 | 0.64 | 3.2 | |
— | 175 ± 8.0 | 1.00 ± 0.04 | 1,520 ± 120 | 0.97 ± 0.06 | 19 ± 4%f | — | NDh | >57 | 8.69 | >6.6 | |
R=CH2CH3, X=H | 27.6 ± 1.7 | 1.29 ± 0.05 | 441 ± 49 | 1.16 ± 0.19 | 2,390; 80%f | 1.12 | NDh | 87 | 15 | 5.8 | |
R=CH2CH3, X=3′,4′-diCl | 3.44 ± 0.02 | 1.90 ± 0.05 | 102 ± 19 | 1.27 ± 0.10 | 286 ± 47 | 1.30 ± 0.10 | NDh | 83 | 30 | 2.8 | |
R=CH2CH3, X=H | 5.51 ± 0.93 | 1.15 ± 0.03 | 60.8 ± 9.6 | 0.75 ± 0.07 | 3,550; 86%f | 0.95 | NDh | 640 | 11 | 58 | |
R=CH2CH3, X=3′,4′-diCl | 4.12 ± 0.95 | 1.57 ± 0.00 | 98.8 ± 8.7 | 1.07 ± 0.07 | 199 ± 17 | 1.24 ± 0.00 | NDh | 48 | 24 | 2.0 | |
— | 6,360 ± 1,300 | 1.00 ± 0.04 | 36 ± 10%c | — | 22 ± 7%f | — | 8,800 ± 870 | >1.6 | — | — | |
i — | 4,560 ± 1,100 | 1.10 ± 0.09 | 534 ± 210c | 0.96 ± 0.08 | 53 ± 6%f | — | 1,060 ± 115 | ~2.2 | 0.12 | ~19 | |
R1=CH2OH, R2=H, X=H | 406 ± 4 | 1.07 ± 0.08 | NDh | — | 31.0 ± 1.5%f | — | 1,520 ± 15 | >25 | — | — | |
R1=CH2OCH3, R2=H, X=H | 89.9 ± 9.4 | 0.97 ± 0.04 | NDh | — | 47.8 ± 0.7%f | — | 281 ± 19 | ~110 | — | — | |
R1=CH2OH, R2=H, X=3′,4′-diCl | 3.91 ± 0.49 | 1.21 ± 0.06 | NDh | — | 276; 94.6%f | 0.89 | 22.5 ± 1.4 | 71 | — | — | |
R1=H, R2=CO2CH3, X=3′,4′-diCl | 363 ± 20 | 1.17 ± 0.41 | NDh | — | 2,570 ± 580 | 1.00 ± 00.1 | 317 ± 46 | 7.1 | — | — | |
R1=CO2CH3, R2=H, X=2′-Cl | 1,740 ± 200 | 0.98 ± 0.02 | NDh | — | 22.2 ± 2.5%f | — | 2,660 ± 140 | >5.7 | — | — |
Values for dl-threo-methylphenidate derivatives are the mean (s.d.) [17] of 3—6 determinations, or are the mean of duplicate determinations. Values of other compounds are the mean—s.d. for 3—4 determinations where indicated, or are results of single experiments which agree with the literature. All binding experiments were done in triplicate. [18]
Compound | DA | DA Uptake | NE | 5HT |
---|---|---|---|---|
Methylphenidate | 84 ± 33 | 153 ± 92 | 514 ± 74 | >50,000 |
o-Bromomethylphenidate | 880 ± 316 | — | 20,000 | — |
m-Bromomethylphenidate | 4 ± 1 | 18 ± 11 | 20 ± 6 | 3,800 |
p-Bromomethylphenidate | 21 ± 3 | 45 ± 19 | 31 ± 7 | 2,600 |
p-Hydroxymethylphenidate | 125 | 263 ± 74 | 270 ± 69 | 17,000 |
p-Methyloxymethylphenidate | 42 ± 24 | 490 ± 270 | 410 | 11,000 |
p-Nitromethylphenidate | 180 | — | 360 | 5,900 |
p-Iodomethylphenidate | 26 ± 14 | — | 32 | 1,800ɑ |
m-Iodo-p-hydroxymethylphenidate | 42 ± 21 | 195 ± 197 | 370 ± 64 | 5,900 |
N-Methylmethylphenidate | 1,400 | — | 2,800 | 40,000 |
d-threo-Methylphenidate | 33 | — | 244 ± 142 | >50,000 |
l-threo-Methylphenidate | 540 | — | 5,100 | >50,000 |
dl-erythro-o-Bromomethylphenidate | 10,000 | — | 50,000 | — |
Cocaine | 120 | 313 ± 160 | 2,100 | 190 |
WIN 35,428 | 13 | — | 530 | 72 |
Nomifensine | 29 ± 16 | — | 15 ± 2 | 1,300ɑ |
Mazindol | 9 ± 5 | — | 3 ± 2 | 92 |
Desipramine | 1,400 | — | 3.5 | 200 |
Fluoxetine | 3,300 | — | 3,400 | 2.4 |
p-hydroxymethylphenidate displays low brain penetrability, ascribed to its phenolic hydroxyl group undergoing ionization at physiological pH.
(–)-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.
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.
(+)-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.
Lobeline is a piperidine alkaloid found in a variety of plants, particularly those in the genus Lobelia, including Indian tobacco, Devil's tobacco, great lobelia, Lobelia chinensis, and Hippobroma longiflora. In its pure form, it is a white amorphous powder which is freely soluble in water.
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.
HDMP-28 or methylnaphthidate is a piperidine based stimulant drug, closely related to methylphenidate, but with the benzene ring replaced by naphthalene. It is a potent dopamine reuptake inhibitor, with several times the potency of methylphenidate and a short duration of action, and is a structural isomer of another potent dopamine reuptake inhibitor, N,O-Dimethyl-4-(2-naphthyl)piperidine-3-carboxylate. It has been sold as a designer drug since around 2015.
2-Benzylpiperidine is a stimulant drug of the piperidine class. It is similar in structure to other drugs such as methylphenidate and desoxypipradrol but around one twentieth as potent, and while it boosts norepinephrine levels to around the same extent as d-amphetamine, it has very little effect on dopamine levels, with its binding affinity for the dopamine transporter around 175 times lower than for the noradrenaline transporter. 2-benzylpiperidine is little used as a stimulant, with its main use being as a synthetic intermediate in the manufacture of other drugs.
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.
Tropoxane (O-1072) is an aryloxytropane derivative drug developed by Organix Inc., which acts as a stimulant and potent dopamine and serotonin reuptake inhibitor. It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link, demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition.
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.
(–)-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.
Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a chemical class of pharmaceutical, designer, and experimental drugs.
3,4-Dichloromethylphenidate is a stimulant drug related to methylphenidate. Dichloromethylphenidate is a potent psychostimulant that acts as both a dopamine reuptake inhibitor and norepinephrine reuptake inhibitor, meaning it effectively boosts the levels of the norepinephrine and dopamine neurotransmitters in the brain, by binding to, and partially blocking the transporter proteins that normally remove those monoamines from the synaptic cleft.
threo-4-Methylmethylphenidate (4-MeTMP) is a stimulant drug related to methylphenidate. It is slightly less potent than methylphenidate and has relatively low efficacy at blocking dopamine reuptake despite its high binding affinity, which led to its investigation as a possible substitute drug for treatment of stimulant abuse. On the other hand, several other simple ring-substituted derivatives of threo-methylphenidate such as the 4-fluoro and 3-chloro compounds are more potent than methylphenidate both in efficacy as dopamine reuptake inhibitors and in animal drug discrimination assays.
Metaphit is a research chemical that acts as an acylator of NMDARAn, sigma and DAT binding sites in the CNS. It is the m-isothiocyanate derivative of phencyclidine (PCP) and binds irreversibly to the PCP binding site on the NMDA receptor complex. However, later studies suggest the functionality of metaphit is mediated by sites not involved in PCP-induced passive avoidance deficit, and not related to the NMDA receptor complex. Metaphit was also shown to prevent d-amphetamine induced hyperactivity, while significantly depleting dopamine content in the nucleus accumbens. Metaphit was the first acylating ligand used to study the cocaine receptor. It is a structural isomer of the similar research compound fourphit, as it and metaphit both are isothiocyanate substituted derivatives of an analogous scaffold shared with PCP.
4-Fluoromethylphenidate is a stimulant drug that acts as a higher potency dopamine reuptake inhibitor than the closely related methylphenidate.
1-Methyl-3-propyl-4-(p-chlorophenyl)piperidine is a drug developed by a team led by Alan Kozikowski, which acts as a potent dopamine reuptake inhibitor, and was developed as a potential therapeutic agent for the treatment of cocaine addiction. As with related compounds such as nocaine, it is a structurally simplified derivative of related phenyltropane compounds. Its activity at the serotonin and noradrenaline transporters has not been published, though most related 4-phenylpiperidine derivatives are relatively selective for inhibiting dopamine reuptake over the other monoamine neurotransmitters. While several of its isomers are active, the (3S,4S)-enantiomer is by far the most potent. The rearranged structural isomer 2-[1-(4-chlorophenyl)butyl]piperidine is also a potent inhibitor of dopamine reuptake.
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