Tropoxane Explained
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 It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link (at the bridgehead position), demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition.[3] [4] [5]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. 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
Notes and References
- Meltzer PC, Blundell P, Chen Z, Yong YF, Madras BK . Bicyclo[3.2.1]octanes: synthesis and inhibition of binding at the dopamine and serotonin transporters . Bioorganic & Medicinal Chemistry Letters . 9 . 6 . 857–62 . March 1999 . 10206550 . 10.1016/s0960-894x(99)00098-0 .
- WO . 9740859 . application . Bridge-substituted Tropanes and Uses . 6 November 1997 . Madras BK, Meltzer PC . Harvard College .
- Madras BK, Pristupa ZB, Niznik HB, Liang AY, Blundell P, Gonzalez MD, Meltzer PC . Nitrogen-based drugs are not essential for blockade of monoamine transporters . Synapse . 24 . 4 . 340–8 . December 1996 . 10638825 . 10.1002/(SICI)1098-2396(199612)24:4<340::AID-SYN4>3.0.CO;2-D . 13410912 .
- Meltzer PC, Liang AY, Blundell P, Gonzalez MD, Chen Z, George C, Madras BK . 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 . August 1997 . 9276012 . 10.1021/jm9703045 .
- Madras BK, Miller GM, Meltzer PC, Brownell AL, Fischman AJ . Molecular and regional targets of cocaine in primate brain: liberation from prosaic views . Addiction Biology . 5 . 3 . 351–9 . July 2000 . 20575852 . 10.1111/j.1369-1600.2000.tb00202.x . 26252206 .
- Pham-Huu DP, Deschamps JR, Liu S, Madras BK, Meltzer PC . 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 . January 2007 . 17070057 . 1829488 . 10.1016/j.bmc.2006.10.016 .
- 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 . Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors . European Journal of Pharmacology . 479 . 1–3 . 41–51 . October 2003 . 14612136 . 10.1016/j.ejphar.2003.08.055 .
- Goulet M, Miller GM, Bendor J, Liu S, Meltzer PC, Madras BK . Non-amines, drugs without an amine nitrogen, potently block serotonin transport: novel antidepressant candidates? . Synapse . New York, N.Y. . 42 . 3 . 129–40 . December 2001 . 11746710 . 10.1002/syn.1108 . 22341553 .
