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

Abstract 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 .