Synthesis of 2β-acyl-3β-aryl-8-azabicyclo[3.2.1]octanes and their binding affinities at dopamine and serotonin transport sites in rat striatum and frontal cortex

Article abstract of DOI:10.1021/jm00035a005

A novel entry to tropane analogs of cocaine was developed on the basis of the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine and serotonin (5-HT) transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3-position was directly bound to the tropane ring (as in WIN-35,428), and methyl or ethyl ketone moieties were present at the 2- position instead of the typical ester group. The series of analogs containing a 2-naphthyl group at the 3-position were most potent, with K(i) values < 1 nM in binding to both dopamine and 5-HT transporters. Although the unsubstituted 2-naphthyl analog was nonselective at dopamine and 5-HT transport sites, other compounds were selective for either site. In general, compounds with relatively small substituents on the aromatic moiety (such as p-methyl or p-fluoro) were relatively selective for the dopamine transporters, while a p-isopropylphenyl derivative was selective for the 5- HT transport sites. This latter compound represents the first N-methyltropane derivative specific for 5-HT transporters. Resolution of two of the most significant analogs was achieved by HPLC on a chiral stationary phase; the active enantiomer of a 2-naphthyl analog exhibited K(i) values of <0.01 nM at both dopamine and 5-HT transporter sites.