SYNTHESIS OF 3-BETA-ARYL-8-AZABICYCLO[3.2.1]OCTANES WITH HIGH BINDINGAFFINITIES AND SELECTIVITIES FOR THE SEROTONIN TRANSPORTER SITE

A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These a nalogs were tested in binding to dopamine, serotonin (5-HT), and norep inephrine transporters in membranes from rat striatum and frontal cart er. In all the analogs, the aryl group at the 3 position was directly bound to the tropane ring and an ethyl ketone moiety was present at th e 2 position. By appropriate modification of the aryl and nitrogen sub stituents highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3 beta-[4-(1-methylethenyl)phe nyl]-2 beta-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a K-i of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT v s dopamine transporters and almost 1000 times more potent at 5-HT vs n orepinephrine transporters.