This is a revised competitive renewal for years 30-33 of a collaborative project with the following goals: (1) To design more potent selective vasopressin (VP) hypotensive peptides. (2) To design high affinity radioiodinatable and fluorescent ligands for the putative VP vasodilating receptor. (3) To design specific antagonists of this receptor. (4) To design selective agonists, antagonists, radioiodinatable and fluorescent ligands for the rat and human VP Vlb receptors. (5) To use the recently discovered constitutively active human VP V2 receptor, to design (a) antagonists, (b) selective radioiodinated ligands and (c) fluorescent ligands for the human V2 receptor. (6) To design OT antagonists which have a higher affinity and selectivity for the human OT receptor than atosiban, the only OT antagonist in clinical use for the treatment of premature labor. (7) To design high affinity fluorescent and rhodamylated ligands for the rat and human OT receptors. (8) To investigate the functional architecture and species differences of the VP Vlb receptors. (9) To continue to """"""""advance the field"""""""" by being a source of VP and OT ligands as research tools for others in the field. The novel selective VP hypotensive peptides may lead to new therapies for treating hypertension. VP Vlb antagonists could be used for the diagnosis and treatment of ACTH secreting tumors. VP V2 antagonists could be of value for the treatment of the syndrome of inappropriate secretion of the antidiuretic hormone (SIADH), congestive heart failure and brain edema. In addition, to their value as tocolytic agents for the treatment of premature labor, OT antagonists may also have potential as radioactive carriers for radioimaging and radiotherapy of OT-receptor expressing tumors. To meet goals 1-8 """"""""State of the Art"""""""" design and synthetic methodology will be utilized in the P.I.'s laboratory. The bioassays required to meet objectives 1-3 will be carried out in the laboratory of Dr. Szeto. The receptor binding and functional assays required to meet objectives 2, 4-8 will be carried out in the laboratory of Dr. Barberis. Letters from Drs. Szeto and Barberis cosigned by colleagues Drs. Guillon, Durroux and Mouillac are attached (see pages 79, 82).
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