Tropoxane

Tropoxane

Clinical data
ATC code	none
Identifiers
IUPAC name Methyl (1R,2S,3S,5S)-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylate
CAS Number	192461-10-2
PubChem CID	9796921
ChemSpider	7972687
ChEMBL	ChEMBL5271116
CompTox Dashboard (EPA)	DTXSID801028338
Chemical and physical data
Formula	C15H16Cl2O3
Molar mass	315.19 g·mol−1
3D model (JSmol)	Interactive image
SMILES Clc1ccc(cc1Cl)[C@H]2C[C@H]3O[C@@H]([C@H]2C(=O)OC)CC3
InChI InChI=1S/C15H16Cl2O3/c1-19-15(18)14-10(7-9-3-5-13(14)20-9)8-2-4-11(16)12(17)6-8/h2,4,6,9-10,13-14H,3,5,7H2,1H3/t9-,10+,13+,14-/m0/s1 Key:DHXANQGCRAVCSQ-PJQZNRQZSA-N
(verify)

Tropoxane (O-1072) ^[1] is an aryloxytropane derivative drug developed by Organix Inc., ^[2] 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 It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link (at the bridgehead position), demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition. ^{[3] [4] [5]}

Thia analog

The 8-thiabicyclo(3.2.1)octanes analogs such as O-4210 have been prepared. ^[6] A representative set of analogs is listed below.

MAT IC50 (nM) 8-thiabicyclo[3.2.1]octanes

X	Com	DAT	SERT	Com	DAT	SERT	Com	DAT	SERT
H	1a	910	>10uM	2a	140	>8uM	3a	117	>3uM
F	1b	220	>30uM	2b	59	>11uM	3b	38	494
Cl	1c	13	>10uM	2c	11	1uM	3c	9.6	33
Br	1d	9.1	>25uM	2d	6.0	342	3d	6.0	14
I	1e	6.7	>8uM	2e	9.0	70	3e	14	10
Cl2	1f	4.5	>3uM	2f	6.9	99	3f	5.7	8.0
BN	1g	8.0	>1uM	2g	8.0	36	3g	16	13

It had been hypothesized that transporter binding of the tropanes might include ionic bonding of the central tropane nitrogen. But it turned out that at this site neither ionic nor hydrogen bonding is a prerequisite for potent monoamine reuptake inhibition. Oxa- and thia-analogs of RTI-111 are potent inhibitors, and even an N-replacement by methylene holds the potency within the same magnitude. ^{[6] [7] [8]} However, N-quaternisation (N-dimethyl) considerably reduces DAT affinity.

In this SAR, the focus is on seeing the effect of changing 8-NMe to S, O, or CH2. Both enantiomers, as well as the racemates are presented in several cases for comparison.

MAT IC50 (nM) Cl2 bicyclo[3.2.1]octanes

Enant.	X	Com	DAT	SERT	Com	DAT	SERT	Com	DAT	SERT
Rac	S	1a	4.5	3,600	2a	6.9	99	3a	5.7	8.0
Rac	O	1a	10	6,000	2a	3.1	64.5	3a	3.3	6.5
1R	NMe	1a	1.2	867	2a	0.4	27	3a	1.1	2.5
Rac	CH2	1a	7.1	5,160	2a	13	166	3a	9.6	33

See also

• List of cocaine analogues
• O-2172

References

1. Meltzer PC, Blundell P, Chen Z, Yong YF, Madras BK (March 1999). "Bicyclo[3.2.1]octanes: synthesis and inhibition of binding at the dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry Letters. 9 (6): 857–62. doi:10.1016/s0960-894x(99)00098-0. PMID   10206550.
2. WOapplication 9740859,Madras BK, Meltzer PC,"Bridge-substituted Tropanes and Uses",published 6 November 1997, assigned to Harvard College 
3. Madras BK, Pristupa ZB, Niznik HB, Liang AY, Blundell P, Gonzalez MD, Meltzer PC (December 1996). "Nitrogen-based drugs are not essential for blockade of monoamine transporters". Synapse. 24 (4): 340–8. doi:10.1002/(SICI)1098-2396(199612)24:4<340::AID-SYN4>3.0.CO;2-D. PMID   10638825. S2CID   13410912.
4. Meltzer PC, Liang AY, Blundell P, Gonzalez MD, Chen Z, George C, Madras BK (August 1997). "2-Carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters". Journal of Medicinal Chemistry. 40 (17): 2661–73. doi:10.1021/jm9703045. PMID   9276012.
5. Madras BK, Miller GM, Meltzer PC, Brownell AL, Fischman AJ (July 2000). "Molecular and regional targets of cocaine in primate brain: liberation from prosaic views". Addiction Biology. 5 (3): 351–9. doi:10.1111/j.1369-1600.2000.tb00202.x. PMID   20575852. S2CID   26252206.
6. Pham-Huu DP, Deschamps JR, Liu S, Madras BK, Meltzer PC (January 2007). "Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry. 15 (2): 1067–82. doi:10.1016/j.bmc.2006.10.016. PMC   1829488 . PMID   17070057.
7. Madras BK, Fahey MA, Miller GM, De La Garza R, Goulet M, Spealman RD, Meltzer PC, George SR, O'Dowd BF, Bonab AA, Livni E, Fischman AJ (October 2003). "Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors". European Journal of Pharmacology. 479 (1–3): 41–51. doi:10.1016/j.ejphar.2003.08.055. PMID   14612136.
8. Goulet M, Miller GM, Bendor J, Liu S, Meltzer PC, Madras BK (December 2001). "Non-amines, drugs without an amine nitrogen, potently block serotonin transport: novel antidepressant candidates?". Synapse. 42 (3). New York, N.Y.: 129–40. doi:10.1002/syn.1108. PMID   11746710. S2CID   22341553.