The broad, long-term objectives of this project are to develop potent, selective opioid antagonists and antagonists that have very limited access to the central nervous system (CNS) upon peripheral administration. The applications of such ligands will e as pharmacologic tools to study the peripheral actions of oploids without the applications arising from centrally mediated effects. Such ligands have many potential research applications, including their use as tools for investigating the immunodulatory, endocrinological, gastrointestinal, renal, and cardiovascular effects of opiods. In this application we propose to synthesize five series of opioid agonists and antagonists which contain ionizable groups derived from amino acids. The ionizable groups in the target compounds are designed to greatly impede access into the CNS upon peripheral administration. In order to confer receptor selectivity, the pharamacophores in the target compounds will be derived from established, nonpeptide ligands with known pharmacologic selectivity for mu, delta, and kappa opioid receptors. The target compounds first will be tested in guinea pig ileal longitudinal muscle and in the mouse vas deferens preparation to evaluate their pharmacologic selectivity and potencies, and then in the receptor binding assay. Target compounds that possess high selectivity and potency will be tested in antinociceptive assays in ice after administration by three different routes (i.c.v., i.v.', and p.o.). The selectivity of these ligands will be evaluated in these in vivo studies and peripheral-CNS potency ratio will be established. Application is made to become a collaborating Diagnostic Center for Psychiatric Linkage Studies (Schizophrenia). Demographically diverse families including affected nuclear families, extended pedigrees, and an American eskimo geographic isolate segregating schizophrenia have been identified and will be ascertained. A subgroup will undergo diagnostic assessment in several domains of psychopathology, as well as psychometric, neuropsychologic, psychophysiologic, neuroradiologic (structural and functional), and psychopharmacologic evaluations. Ultimately, combining these biobehavioral assessments with linkage results may allow for the identification of endophenotypes, characterization of homogenous subtypes, clarification of epigenetic factors, and recognition of premorbid pathophysiology in schizophrenia
