The long-term objective of this research project is to discover and develop novel non-peptide opioid ligands with the potential for use as drugs for the treatment of pain, drug addiction, and related disorders. Opioid drugs currently in use as potent analgesics mediate their action primarily through mu receptors. The use of these drugs is severely limited by serious side effects such as respiratory depression, development of tolerance, dependence, and addiction liabilities. Several lines of evidence indicate that opioid ligands possessing a mixed profile of agonist action at the mu receptors and antagonist action at the delta receptors may prove to be novel analgesic agents devoid of these side effects. In our earlier efforts we have identified lead compounds possessing mixed mu agonis V delta antagonist profile of activity and have found them to display analgesic activity with less propensity to produce tolerance, thus supporting the validity of the concept. These results have provided the foundation for continued research in this direction with the specific goal of improving the mu agonist characteristics of the lead compounds while retaining or improving the delta antagonist activity. Towards achieving this goal, we will now pursue the synthesis and evaluation of model based, rationally designed ligands possessing the epoxymorphinan template. The two approaches that have been used to design new target molecules are based on (1) 3D-QSAR predictions for mu agonist and delta antagonist activities, and (2) pharmacophoric hypothesis involving conformational and structural similarities between the morphinan template and peptides with similar interaction profiles. The evaluation of the new ligands will consist of determinations of binding affinity at the opioid mu, delta, and kappa receptors and for in vitro agonist and antagonist functional activity in GTP binding assays using cells expressing cloned human opioid receptors. Compounds with promising profiles of activity will be evaluated in vivo in mice for analgesic activity as well as to assess tolerance and dependence liability, and to establish receptor selectivity profiles in vivo. The continuation of the collaborative effort should lead to the discovery of promising ligands useful as pharmacological tools and as drugs for treatment of pain and drug abuse. Moreover, the analysis of the binding affinity and activity profile of the new ligands using computer-assisted methods should enhance our fundamental knowledge regarding structural determinants of ligand recognition and functional activation at the opioid receptors. ? ? ?
