The goal of this application is to develop biochemical probes for use in gaining a better understanding of biochemical and molecular mechanisms of analgesic addiction withdrawal. The specific objectives include: (1) the development of a class of opioid antagonists based on N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)-piperidines; (2) the design of target compounds based on the above model; and (3) the receptor binding evaluation of the target compounds designed to determine selectivity for mu, delta, kappa1, kappa2b opioid receptors. Compounds that show delta selectivity will be evaluated in antinociceptive assays for delta1 and delta2 selectivity. Selected compounds will be tested for aversive and reinforcing properties in the conditioned-place preference assays. In addition, compounds which have Ki values less than 100 nM at any of the opioid receptors will be submitted to the CPDD testing program and the NIDA Drug Discovery Program. In order to accomplish the goals above, RTI, with help from Dr. Zimmerman (Eli Lilly), will design and synthesize the target compounds. Valuable starting materials will also be provided by Eli Lilly. Drs. Rothman (NIDA-ARC), Porreca (University of Arizona), and Shippenberg )NIDA-ARC) will provide the receptor binding, antinicociceptive, and behavioral studies, respectively. At present, few potent, systematically active and selective nonpeptide antagonists are available. The design and synthesis of novel selective nonpeptide opioid receptor antagonists will provide critically needed tools to advance our understanding of the role of the opioid receptor/endorphin system in both normal and various disease states, including drug addiction. In particular, we propose that the development of selective delta and kappa antagonists may provide a new generation of important investigational drugs and possible treatment drugs for people suffering from drug addiction.
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