This is a competitive renewal of an ongoing collaborative project with Wilbur H. Sawyer, Professor of Pharmacology, College of Physicians and Surgeons, Columbia University of New York, on the design and synthesis of antagonists of the neurohypophysial peptides, arginine vasopressin (AVP) and oxytocin (OT). The goals of this proposal are to exploit leads uncovered during the past award period towards meeting the following objectives; 1. To synthesize potent, selective and long-acting antagonists of the vascular (VI - receptor) responses to AVP. 2. To synthesize potent, selective and orally active antagonists of the antidiuretic (V2 - receptor) responses to AVP. 3. To synthesize, potent, selective and long acting antagonists of the uterine contracting responses to oxytocin. Such antagonists can be powerful tools in studies on the physiological roles of AVP and OT under norma) and pathophysiological circumstances. AVP V2 antagonists could be of therapeutic value for the treatment of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH); adrenal insufficiency, cirrhosis, congestive heart failure and brain edema. OT antagonists may be helpful in the prevention of premature labor and AVP VI antagonists may be useful in the treatment of some forms of hypertension. To reach these goals, two interrelated approaches will be followed. A. Our best cyclic antagonists will be further modified. 8. Our recently discovered linear antagonists will be vigorously explored and modified. Modifications in A and B will include D and L amino acid substitutions, N and C terminal extensions, deletions, peptide-bond isostere insertions, peptide chain cyclizations, etc. 4. We will also vigorously reexamine the question of whether or not a cyclic conformation is required for the activation of AVP and OT receptors. 5. With Dr. Serge Jard, CNRS, Montpelier, France, we will continue to search for specific radioiodinated Tyr(L and D) ligands for AVP and OT receptors. Peptides are synthesized in my laboratory and pharmacologically evaluated in Dr. Sawyer's laboratory. Some will also be evaluated by Dr. S. Jard in binding, adenylate cyclase activation and phosphatidyl inositol turnover assays. 6. We will continue to supply peptides to other investigators for their independent studies on the roles of AVP and OT under normal and pathophysiological states.
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