The significance of kappa and sigma opioid receptors as well as mu in the drug abuse field has become increasingly recognized. Study of the physiological effects of these receptor systems depends on the availability of selective antagonists. For kappa receptors the only commercially available kappa-selective competitive antagonist is nor-BNI which is slow in onset and of very long duration. There are few reports of in vivo studies with any of the more recently reported selective kappa-antagonists. It is important that a greater range of such agents both competitive and noncompetitive become available. This application aims to provide them. Nor-BNI and analogous ligands having twin basic centers were designed by application of the message-address concept. Preliminary studies have shown that the location of this second basic center in nor-BNI and its analogs is not optimum for kappa-selectivity. This structural feature will be extensively explored as will the significance of a lipophilic binding site located close to that for the second basic center. Another approach to the design of selective kappa-antagonists utilizes the recent discovery of a new kappa-antagonist pharmacophore related to the kappa-agonist ICI 197067. When attached to the robustly antagonist phenylpiperidine structure, kappa-selectivity was introduced. Other structures associated predominantly with opioid activity have been identified for elaboration with the new pharmacophore. In the case of N-CPM-14-aminomorphinone this objective will be pursued in collaboration with the RTI group. The only reported kappa-selective irreversible antagonists show initial kappa-agonism since they are based on kappa - agonist structures onto which an electrophilic group has been introduced. Structures with potential for competitive kappa-antagonist selectivity have been identified onto which an electrophile can be substituted. It is intended to use the non-competitive selective kappa- antagonists to establish procedures for the determination of the relative efficacies of a range of standard kappa- agonists and some orvinol analogs of buprenorphine using antinociceptive and drug discrimination assays. The latter will involve collaboration with Dr Mitchell Picker, University of North Carolina, Chapel Hill.
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