Synthesis, structural identification, and ligand binding of tropane ring analogs of paroxetine and an unexpected aza-bicyclo[3.2.2]nonane rearrangement product Original Research Article

The structural requirements for high affinity at the serotonin transporter (5-HTT) have been investigated through the preparation of rigid paroxetine analogs. Tropane-derived analogs (4a–i) of paroxetine (2) were designed and synthesized as potential inhibitors of serotonin reuptake based on the structural and biological similarity between the two compound classes. Overall, the affinity of tropane-derived analogs at the 5-HTT was found to be at least an order of magnitude lower than that of paroxetine and ranged from 2–400 nM. The reduced affinity at the 5-HTT may be attributed to the inability of the rigid tropane-derived analogs to adopt conformations favored by the 5-HTT. Within the series of tropane analogs, the 2β,3β- and 2β,3α-isomers, 4a and 4d, were the most potent at the DAT and NET and are also significantly more potent than paroxetine (2) suggesting that their reduced conformational flexibility maximizes residence time in conformations favored by these transporters. Examination of the previously published preparation and structural assignment of 4a by additional NMR and X-ray crystallographic data has established that nucleophilic addition to the intermediate 2β-methanesulfonyloxymethyl-3β-(4-fluorophenyl)tropane unexpectedly provided the aza-bicyclo[3.2.2]nonane derivative 10a.