Objectives of Present Proposal: To capitalize on the progress achieved during the past award period in collaboration with Dr. Wilbur H. Sawyer, Professor of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, in studies on the design, synthesis and testing for potential clinical applications of the following: 1) Potent and selective antagonists of the antidiuretic responses to (AVP) for use as a) pharmacological tools for studying the contribution of vasopressin to water retention in normal and pathophysiological states, and b) therapeutic agents for the treatment of hyponatremias. 2) Potent and selective antagonists of the vasopressor responses to vasopressin for use in studies on the roles of vasopressin in regulating blood pressure under normal and pathophysiological states. 3) Potent and selective antagonists of in vivo oxytocic and milk-ejecting responses to oxytocin for possible use in the prevention of premature deliveries and as pharmacological tools. The proposed studies will focus on maximizing, potency, selectivity and duration of action by chemical modifications of the best lead compounds developed to date. The peptides will be synthesized in the P.I.'s laboratory. The pharmacological testing will be carried out in Dr. Sawyer's laboratory. Additional Objectives are: 4) In collaboration with Serge Jard, to correlate the in vivo potencies of selected AVP agonists and antagonists with their in vitro properties in binding and adenylate cyclase activation assays and to thus gain additional insights into the topochemical facets of neurohypophyseal peptide agonists and antagonists involved in a) binding and/or b) activation of specific receptors in a variety of tissues and c) prolonging their duration of action. 5) To continue to provide other investigators with samples of synthetic peptides for their independent investigations. Peptides from the P.I.'s laboratory have been and continue to be very useful pharmacological probes of the physiological roles of AVP and oxytocin.
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