Formerly projects: Z01 DK 19226-08LC, Z01 DK 19202-13LC, Z01 DK 19237-05LC, Z01 AM 19239-04LC, Z01 DK 19246-04LC Z01 DK 19233-07LC, and Z01 DK 19235-05LC. Recent recognition that the effects of diverse classes of pharmacological agents are mediated by discrete cell receptors, which normally function in concert with their endogenous ligands, has presented unique opportunities for dramatic advances in the understanding of many central and peripheral regulatory systems in animals and humans. Optimal exploitation of such opportunities requires design and synthesis of highly selective drugs as probes for study of these systems and a collaborative, multidisciplinary approach in such studies. Elucidation of the exact molecular structure and mechanism of action of these endogenous ligand-receptor systems, and the molecular mechanism of action of endogenous ligand-mimetic drugs and their antagonists will provide new opportunities for therapeutic intervention in many clinical situations and for the design of superior drugs, particularly for disorders which are now little-understood. Studies in progress are currently aimed at identification, purification, and elucidation of the structure and function of opiate, benzodiazepine and phencyclidine receptor subpopulations in the overall modulation of the CNS. These studies require synthesis of new receptor ligands for several lines of investigation utilizing: (1) irreversible ligands specific for receptor subpopulations; (2) high specific activity radiolabeled ligands for autoradiographic visualization of receptors; (3) conformationally restricted analogs of potent receptor ligands as topological probes; (4) position emission transaxial tomographic visualization of receptor patterns in living brains. Studies designed to identify a clinically useful antagonist of PCP are underway. Synthesis of previously inaccessible unnatural opiate enantiomers using the recently developed NIH Opiate Total Synthesis is also in progress with the goals of identification of new pharmacological agents and effects of opiates mediated through nonclassical opiate receptors.
