Synthesis and biological properties of new 2 beta-alkyl- and 2 beta-aryl-3-(substituted phenyl)tropane derivatives: Stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters

In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, we have been involved in efforts to further el ucidate the nature of cocaine's binding to the dopamine transporter (DAT) t hrough strategic modifications of its :structure. In the case of the substi tuent located at the 2-position of the tropane ring, studies have revealed the ability of the transporter to accommodate groups of diverse structure, including ester, ketone, alkyl, alkenyl, heterocyclic, and aryl substituent s, without loss of DAT binding affinity. In the present study, we report ou r results pertaining to the ability of the DAT to accommodate the WIN-type structures possessing alkyl or aryl groups at the 2-position and which adop t either a chair or a boat conformation of the tropane ring. Moreover, we d iscuss the influence of the stereochemistry of these compounds in their sel ectivity for the DAT versus the serotonin transporter (5HTT). Additionally, we point out the importance of using Ki values rather than IC50 values whe n making such comparisons of transporter selectivity. One of the most inter esting compounds identified in the present work is a 2,3-diaryltropane 22 i n a boat conformation that is highly selective (69-fold) for the DAT over t he 5HTT. The ability to prepare this compound as well as related structures by our oxidopyridinium betaine-based dipolar cycloaddition strategy furthe r underscores the versatility of this particular chemical approach to the p reparation of diverse tropane analogues. The use of the optically pure olef in p-tolyl vinyl sulfoxide as the dipolarophile in this reaction allows acc ess to these novel tropanes in nonracemic form.