 | |
| Clinical data | |
|---|---|
| ATC code |
|
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C15H16Cl2O3 |
| Molar mass | 315.19 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
| (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 It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link (at the bridgehead position), demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition.[3][4][5]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
[edit]The 8-thiabicyclo(3.2.1)octanes analogs such as O-4210 have been prepared.[6] A representative set of analogs is listed below.
| 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.
| 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
[edit]References
[edit]- ↑ 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.
- ↑
- ↑
- ↑ 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.
- ↑
- 1 2
- ↑
- ↑ 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.