This Project application is a broad collarative effort on the part of seven investigator in four institutions to study the hypothesis that opioid delta (delta) receptor subtype-selective agonist, partial agonist and antagonists may be feasible candidates for development as therapeutic agents related to the treatment of pain and addiction. These investigator bring expertise ranging from extensive experience in synthetic chemistry and molecular modeling, in pharmacological analysis of molecules in vitro and in vivo, in application of molecular techniques, to evaluation of behavior in several species including primates. Emphasis in this effort will be two-fold. First, the investigator will attempt to discover, and evaluate in several species, highly receptor subtype-selective delta ligands through a synthetic/pharmacological collaboration in order to test the underlying hypothesis. Second, the novel ligands, and other available pharmacological tools, will be employed to explore in greater detail the pharmacology and physiology of subtypes of opioid delta receptors. Strong collaborative interaction already exists and will be emphasized.
The specific aims are to: (a) synthesize novel, non-peptidic opioid delta subtype-selective ligands using state-of-the-art synthetic, analytical and modeling technology with emphasis on development of a structure- activity relationship for delta subtypes, creation of affinity ligands for characterization and localization of the receptors, and radio ligands for PET and SPECT applications; (b) to synthesize sufficient quantities of these compounds for the biological projects; (c) to evaluate the novel non-peptidic molecules for their receptors selectively in vitro and to characterize them in the Biological Evaluation Core; (d) to evaluate the pharmacology of selective novel non-peptidic agonist using approaches in vivo in antinociceptive, gastrointestinal and behavioral endpoints in mice, rats, pigeons and monkeys; (e) to determine the affinity and activity of the new compounds at the cloned opioid delta receptor(s) following transfection of the receptors to cell lines, with particular emphasis on the human delta receptor(s); (f) to determine the second messenger systems involved in the mechanisms of action of compounds acting selectively at delta receptor subtypes in the naive and opioid- exposed tissue; (g) to evaluate the pharmacology of the selective novel non-peptidic antagonists following repeated exposure alone or in combination with opioids or cocaine using place pairing and self- administration paradigms; (h) to perform detailed pharmacological studied of the possible development of physical dependence via the delta receptor; and (i) to collaborate with outside consultants to obtained any data necessary to assess the central hypothesis of potential clinical importance of opioid delta ligands. It is expected that this multidisciplinary effort will result (a) in a realistic assessment of the therapeutic potential of opioid delta receptors subtype-selective ligands, (b) in the discovery of molecules with potential for development as therapeutically useful substances, and (c) in the advancement of our understanding of the role of opioid delta receptors and their subtypes in normal and pathological physiology.
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