This is a competitive renewal for years 26-29 of a collaborative project which embraces the following specific aims: (1) to explore the structure activity relationships (SAR) of our recently discovered novel vasopressin (VP) hypotensive peptides; (2) to design specific antagonists of these novel hypotensive peptides; (3) to design and synthesize high affinity and selective radioiodinated ligands for the localization and characterization of the putative VP vasodilatory receptor; (4) to design antagonists and high affinity radioiodinated ligands which are selective for the VP V1b receptor; (5) to enhance the potency and selectivity of lead VP V2 antagonists; (6) to design radioiodinated antagonist which is selective for the human V2 receptor; (7) to enhance the potency and receptor selectivity of lead oxytocin (OT) receptor antagonists; (8) to continue to investigate the molecular interaction involved in agonist and antagonist binding and selectivity in the vasopressin/oxytocin receptor family; (9) to synthesize sufficient quantities of lead V2/V1a and OT antagonists for crystallization studies; (10) to continu to supply other investigators with samples of published and unpublished peptid agonists, antagonists and radioligand precursors, at no cost, for their own independent studies. VP V2 antagonists would be of therapeutic value for the treatment of the syndrome of inappropriate secretion antidiuretic hormone (SIADH), congestive heart failure and brain edema. OT antagonists may be helpful in the prevention of premature labor and for the treatment of dysmenorrhea. The novel VP hypotensive peptides may be useful in the treatment of some forms of hypertension. To meet goals 1-7, promising leads from the pas award period using a combination of modern peptide design methods and established SAR approaches will be explored. These efforts will also be guided by data from objectives 8 and 9. Peptides will be designed, synthesized and purified in the PI""""""""s laboratory. In vitro and in vivo bioassays will be carrie out in Dr. Chan's laboratory. Receptor assays and studies will be carried out in the Barberis and Tribollet laboratories. Letters from Drs. Chan, Barberis and Tribollet are attached.
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