The broad long-term objectives of this project are to develop selective affinity labels which can be employed both as pharmacologic and biochemical probes for different opioid receptor types. The requirements are that each of the ligands should be effective both pharmacologically and as an affinity label in vivo so that pharmacologic and biochemical studies can be more reliably correlated. Because opioid antagonists are more useful than agonists in the pharmacologic characterization of opioid receptor types, the target affinity labels will possess selective opioid antagonist activity. Our long-term objectives include utilizing such ligands as tools in opioid research. In the present application these affinity labels will be designed to be selective for kappa or for delta opioid receptors. This will be accomplished through the synthesis of ligands that are structurally related to the kappa-selective antagonist, nor-BNI, and to the delta-selective antagonist, NTI (series A and B, respectively). Members of both series will contain a variety of electrophilic moieties in an effort to optimize covalent bond formation with a single opioid receptor subpopulation. These ligands will be tested for selective, irreversible opioid antagonist activity on smooth muscle preparations, and compounds that fulfill the requirements of irreversibility and selectivity will be evaluated in the binding assay. Affinity labels that possess the appropriate in vitro characteristics will be tested in mice for sustained and selective opioid antagonist activity and for irreversible binding to brain tissue.
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