The Narcotic Drug and Opioid Peptide Basic Research Project enters its 25th year with substantial personnel changes and renewed vigor and enthusiasm. The overall mission of th project in the upcoming funding period is to evaluate compounds with potential for the treatment of opioid abuse. Three medications will receive intense scrutiny in the primate in vivo projects described. Buprenorphine, a drug already in clinical trials, will be evaluated for th time course of its opioid agonist and antagonist effects in measures of analgesia, respiratory depression, rate-decreasing effects, drug discrimination, and reinforcing effects in rhesus monkeys. These results will be compared with those on methoclocinnamox, a drug with a similar profile of initial agonist and late developing antagonist actions. Important differences between this compound and buprenorphine will be sought for primarily in the duration of antagonist actions. The pattern of agonist and antagonist effects under conditions of chronic administration of these two drugs will also be determined. The third compound is buprenorphine adipate, an orally available """"""""pro-drug"""""""" for buprenorphine. We have not evaluated this compound in any assay system as yet, but think its prospects as a treatment for opioid abuse are particularly encouraging. Its slow onset of agonist effects may make it particularly useful in certain populations of opioid abusers. It will be evaluated following both subcutaneous and oral administration to provide an understanding of its pharmacodynamics under both conditions. In addition to the behavioral assays in rhesus monkeys, a drug discovery component is included and involves 1 synthesis of potentially receptor- selective agonists and antagonists, and drugs with long lasting agonist and antagonists effects, 2) evaluation of these drugs in receptor binding and smooth muscle assays and 3) evaluation of these drugs in mouse analgesia assays. Particularly interesting compounds will be tested further in the monkey. Evaluation of the signal transduction properties of opioids in cloned cell lines with mu, kappa, delta receptors is also included in this proposal. At the other end of the spectrum, the human pharmacology of buprenorphine will be evaluated in opioid abusers, with an aim of tracking some of the same phenomena being studied in the monkeys. The ability of buprenorphine to produce dose-related reduction in opioid self administration will be determined and any change in this capacity during chronic administration will be observed. This represents a uniquely broad range of medication development and evaluation, starting with chemical synthesis signal transduction, smooth muscle effects, analgesic effects in mice an monkeys, through dependence, discriminative reinforcing, respiratory effects in monkeys, and beginning studies in human addicts. Interactions among investigator and data at each of these levels should create an enormously productive effort towards increasing the number of useful compounds for the treatment of opioid abuse.
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