Cocaine is a psychomotor stimulant with rewarding or """"""""reinforcing"""""""" property. The pharmacological effect responsible for the rewarding and hence the abuse liability is an section on the dopamenergic synapses. Cocaine prolongs the activity of dopamine in the synapse by blocking the dopamine receptor mechanism. The potency of cocaine and cocaine-like drugs in self- administration studies correlates with their potencies in inhibiting 3H-mazindol binding to the dopamine uptake site in the rat striatum. Since there is no correlation for binding to a large number of other pre-and post-synaptic binding sites the cocaine receptor related to substance abuse appears to be the one associated with dopamine uptake inhibition. In this study the design, synthesis and receptor binding evaluation of cocaine analogs are proposed as a method of investigating the biochemical mechanism of cocaine abuse liability. Molecular modeling studies were used to investigate the conformational energetics of possible pharmacophore binding modes for cocaine and to design the cocaine analogs proposed for study. Since the unique structural and stereochemical requirements seen in biological systems are due to a complementary three- dimensional interaction between a drug and its receptor site, the experimental determination of these requirements can be used to construct a picture of the receptor. This information will provide new and unique tools for biochemical studies and could translate into new agents for the treatment of cocaine addiction.
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