A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine, serotonin (5-HT), and norepinephrine 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 and an ethyl ketone moiety was present at the 2 position. By appropriate modification of the aryl and nitrogen substituents, highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3 beta-[4-(1-methylethenyl)phenyl]-2 beta-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a Ki of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT vs dopamine transporters and almost 1000 times more potent at 5-HT vs norepinephrine transporters.
Synthesis of 3β-Aryl-8-azabicyclo(3.2.1)octanes with High Binding Affinities and Selectivities for the Serotonin Transporter Site. -The tropane analogues (III) and (IV) of cocaine are synthesized and tested in binding to dopamine, serotonin and norepinephrine transporters. The most potent and selective compound is (IIId). -(DAVIES, H. M. L.; KUHN, L. A.; THORNLEY, C.; MATASI, J. J.; SEXTON, T.; CHILDERS, S. R.; J. Med.
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