Immediate therapies are needed for the treatment of cocaine abuse worldwide. In this direction, we recently identified a piperidne-based analog of cocaine (specifically, the trans isomer of 1-methyl-4-(4-chlorophenyl) piperdine-3-carboxylic acid methyl ester) that binds to the cocaine recognition site with comparable affinity to cocaine; additionally, this compound acts as an inhibitor of dopamine uptake. In spite of the compound's potency, it has been observed that in discrimination studies in rats, the compound exhibits only weak cocaine-amphetamine-like effects. Unlike cocaine, this compound has weak motor stimulant effects and is not self administered by rats. These results appear to be promising from the standpoint of discovering a possible medication for drug abuse treatment. In order to properly follow up on these encouraging preliminary results, the investigators plan to conduct further chemical analog synthesis, in vitro pharmacological studies, and in vivo animal experiments on the 4-phenylpiperidine analogs with the objective to improve upon the biological profile of this compound. Within the context of this proposal, it is our intention to pursue the following specific aims: 1. To conduct additional structure-activity relationship studies in order to establish that they are advancing the best compound(s) as possible medications. These studies would include preparation of the lead structure in optically pure form, and the design and synthesis of related analogs embodying a the following structural changes: a) modification of the nature and position of the substituent borne by phenyl ring; b) replacement of the N-methyl group by other alkyl groups and sulfonyl groups, as well as isosteric replacement of NMe by CH2 and O; c) replacemnt of the ester group by alkyl and alkenyl groups. 2. To characterize all newly synthesized analogs pahamacologically in in vitro binding experiments, and for the inhibition of the 5HT, NE, and DA uptake. 3. For selected compounds, to evaluate the intravenous safety of the candidate compounds, and for compounds meeting the saftey critieria, to carry out locomotion activity assays. 4. For compounds meeting set criteria, to further evaluate their behavioral pharmacological profile in animals using intravenous drug self-administration and drug discrimination procedures.
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