This project will support the design and introduction of highly selective nonpeptidic delta opioid agonist as analgesics, medicines for prevention and treatment of opiate dependence, and as antidiarrheal drugs. The anticipated advantage of delta agonist is lack of constipating or other adverse gastrointestinal effects at full analgesic doses. Newly synthesized compounds that exhibits favorable analgesic properties will be rapidly and economically evaluated in mice by three routes of administration for effects on gastric emptying, small intestinal transit, and one enteropooling (a measure of effects on mucosal transport of salt and water). The routes of administration to be employed are oral, system injection (i.p.) and intracerebral injection (i.c.v.). The studies will feature dose-response and time-response evaluations of potency, bioavailability, and pharmacodynamic duration of action. Results will be employed by the chemists in further molecular design. Selected compounds that show exceptional promise, based on analgesia and gastrointestinal profiles in mice, will be subjected to definitive studies in rats with three routes of administration (p.o., i.p.,i.c.v.) to determine drug effects on regional contractile activity and propulsion in the stomach, small intestine, cecum, and colon. The delta opioid patten of activity with these endpoints is established and clearcut pharmacological goals are presented. The techniques to be employed are ongoing and have proven predictive value in humans.
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