A wide variety of physiological and pharmacological actions are mediated by the opiate receptors of the central nervous system. Among the three well established classes of opiate receptors (mu, delta, kappa) recent research efforts have focused attention on the delta subtype of receptors. A large body of evidence indicates that the delta receptors are involved in mediating spinal and supraspinal antinociception, gastrointestinal transit and in modulating the development of tolerance and dependence to opioid and other drugs of abuse such as cocaine. A significant development in the opioid delta receptor pharmacology is the recent biochemical and pharmacological delineation of subtypes of delta receptors which have been termed the delta/1 and delta/2 subtypes or the delta/ncx and delta/cx receptors. Recent studies suggest that heterogeneity exists among these subtypes of delta receptors and further studies may eventually lead to their classification into additional subtypes. The identification of subtypes of opioid delta receptors is an exciting new development which provides opportunities for development of subtype selective drugs for therapeutic applications as novel analgesics (devoid of gastrointestinal, respiratory and drug dependence side effects) and as treatment drugs for problems related to drug additions. The development of agonist and antagonist ligands with high selectivity for the various subtypes of opioid delta receptors is of primary importance since stable and selective ligands are needed for use as pharmacological tools and as selective drugs with minimal side effects. A long term objective of the proposed work is the development of stable nonpeptide ligands with specific agonist or antagonist activity and high selectivity for these various delta receptor subtypes. In an effort to achieve these goals, proposed herein is a collaborative effort involving drug design, synthesis and in vitro and in vivo evaluations in isolated tissues and in animal models. An approach that has been adopted in the design of novel ligands is to utilize the recent observations of delta selectivity for some of the morphinan derivatives as a starting point for rational structural manipulations that might impart desired efficacy and selectivity for the delta receptor subtypes. The synthesis and evaluation of the envisioned indolo-, pyrido- and pyrimidomorphinan target compounds should provide new insights regarding the ligand binding characteristics of the opioid delta receptor subtypes. Moreover, the proposed studies should aid in the identification of new delta receptor subtype selective agents that may potentially be useful as analgesics and as therapeutic agents for the treatment of tolerance and dependence problems associated with drugs of abuse.
