Synthesis and pharmacology of potential site-specific cocaine abuse treatment agents: The role of the phenyl group in 2-substituted-6-aminobicyclo[2.2.2]octanes

A previous study led to the development of (1R/S, 4R/S)-5R/S-phenyl-6R/S-(N,N-dimethylamino)bicyclo-[2.2.2]octan-2S/R-yl benzoate (6) as a potent inhibitor of [H-3]WIN 35,428 (WIN) binding to the dopamine transporter (DAT). Since compound 6, which contains a benzoate ester at the C-2 position, was more potent than compounds bearing other substitutions at this position (e.g. a ketone, secondary alcohol, or an acetate ester) the role of the second benzene ring in the binding interaction with the DAT was not obvious. Several new 2-substituted-6-aminobicyclo [2.2.2] octanes were therefore synthesized and tested for inhibitor potency in WIN binding and inhibition of [H-3]DA uptake In addition, the inhibitor potency was also tested using [H-3]paroxetine binding assays for the serotonin transporter (5-HTT) to demonstrate transporter selectivity. Placing a 3-chloro- or a 4-chlorobenzoate at the C-2 position did not markedly change the potency of either WIN binding or DA uptake. However, placing a 4-chloro substituent on the phenyl at the C-5 position provided a more potent congener than compound 6. Complete removal of the phenyl ring at C-5 resulted in drastic reduction in WIN binding affinity. The data obtained provided further evidence that supports the hypothesis that these compounds bind through a primary interaction at the C-5 phenyl on the bicyclic with the "aromatic ring binding site" on the DAT.