2,3-Disubstituted 6-azabicyclo[3.2.1]octanes as novel dopamine transporter inhibitors

A series of cis and trans 3β-aryl-2-carbomethoxy-6-azabicyclo[3.2.1] octanes, with different substitution at the para-position of the aryl group, were synthesized and examined for reuptake inhibition at the dopamine transporter (DAT). The potency for inhibition of DA reuptake was compared with that of cocaine to determine the significance of the replacement of the 8-azabicyclo[3.2.1]octane (tropane nucleus), displayed in cocaine, for the 6-azabicyclo[3.2.1]octane (normorphan framework). This bicyclic core structure constitutes a novel chemical scaffold in DAT inhibitor design, which may provide new insights into the 3D structure of the DAT and its interaction with cocaine and DA. Among these compounds, the trans-amine series 8 were the most potent ligands at the DAT. In particular, the normorphan analogue 8c (bearing a p-chloro substituent at the β-aryl group, IC₅₀=452 nM) displayed a potency that is in the same range as cocaine (IC₅₀=459 nM) itself.