The basic premise of this proposal is that the cocaine recognition site and the dopamine uptake site are not identical. If this notion is correct, and indeed we have acquired further data to support this possibility (Preliminary Studies) then it may well be possible to discover cocaine analogues which can bind to the cocaine recognition site but unlike cocaine, fail to inhibit or only weakly inhibit the reuptake of cocaine through the associated dopamine transporter. The discovery of such partial agonists or antagonists of cocaine may be valuable from a therapeutic standpoint, for such compounds: (1) may be used to counter some of the adverse side effects of cocaine in cases of cocaine overdose; or (2) may lead to the development of a """"""""cocaine antagonist"""""""" for use in maintaining patients in treatment programs. Other uses for functionally altered analogues of cocaine can also be envisioned including the possible application of such compounds to diseases like schizophrenia. To better get at the root of cocaine abuse and to develop more directed strategies for treatment, we believe it essential to continue our efforts to learn more about the basic chemistry and pharmacology of cocaine. Accordingly, we believe it most important to base our program on the discovery of the structural-functional relations that govern cocaine's pharmacology.
The specific aims of this combined chemical synthesis/pharmacology program are as follow: (1) to synthesize selected analogues of cocaine in order to obtain a more complete understanding of its structure activity relationships; particular emphasis will be placed on the further exploration of compounds found to exhibit a weak antagonistic action; (2) to pharmacologically characterize all newly synthesized compounds by studying their properties in mazindol binding studies and on dopamine synaptosomal uptake as well as release in slices; and (3) in cases where compounds of unusual activity are found, to examine the effects of the new analogues in paradigms in which the potential antagonism of cocaine's action on dopamine uptake and release could be realized. The information obtained from the specific aims delineated above will serve: (a) to provide further information as to the bound conformation of cocaine at its recognition site(s); (b) to reveal details of the topography of these sites; and (c) to identify structural features which may be relevant to the discovery of cocaine partial agonists and antagonists. Results of our efforts to date which include the discovery of a weak cocaine antagonist are detailed in the Preliminary Studies Section.
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