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 It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link (at the bridgehead position), demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition.
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 SERTH 1a 910 >10uM 2a 140 >8uM 3a 117 >3uMF 1b 220 >30uM 2b 59 >11uM 3b 38 494Cl 1c 13 >10uM 2c 11 1uM 3c 9.6 33Br 1d 9.1 >25uM 2d 6.0 342 3d 6.0 14I 1e 6.7 >8uM 2e 9.0 70 3e 14 10Cl2 1f 4.5 >3uM 2f 6.9 99 3f 5.7 8.0BN 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. 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