The long term objectives of this project are the development of novel nonpeptide ligands with specific agonist or antagonist activity at the opioid receptors and their subtypes with the potential for use as phamtacological tools and as therapeutic agents. A large body of evidence indicates that the opioid & receptors are involved in mediating spinal and supraspinal antinociception, and in rnodulating the analgesic and tolerance and dependence effects of () agonists such as morphine. In our collaborative effort we have discovered that heteroaromatic ring-fused morphinans such as the pyridomorphinans can serve as suitable templates for the development of novel high affmity ligands for the opioid (gama)receptors, and that strategic placement of aromatic substituents on this framework can provide not only potent o receptor antagonists, but also ligands possessing rnixed (gama) antagonist/() agonist properties. Interest in compounds with such mixed () agonist/ (gama) antagonist properties stans from recent endence indicating that they have the potential to ernerge as novel analgesics devoid of tolerance and dependence side effects. A major goal of the research proposed herein is to pursue the design, synthesis and evaluation of novel ligands based on the lead compounds with the specific aims of (A) identifying ligands with a balanced profile of () agonistl o antagonist properties, (B) identifying ligands with superior (gama) antagonist selectivity than the prototypes, and (C) developing structure-activity correlations to gain an insight into ligand-receptor interactions. The new ligands to be pursued involve rational modifications to the lead structures including systernatic substituent group variations, introduction of conformational restraints as well as exploration of effect of substitutions at sterically tolerant positions thTough the synthesis of srnall, focused libraries of compounds. The evaluations to be carried out on these compounds will include (i) evaluation of opioid receptor binding affmities in radioligand binding assays (ii) evaluation of efficacy profile in vitro in biochemical assays and (iii) phannacological evaluations in vivo to profile analgesic, tolerance and dependence effects of promising ligands. This comprehensive approach should lead to the identification and development of drugs that could provide new approaches to the treatment of chronic pain and for the teatrnent of problems associated with drugs of abuse.
