This is a competitive renewal of a long-standing collaborative project focused on the design and synthesis of A) cyclic and linear peptide agonists and antagonists of arginine vasopressin (AVP) and of oxytocin (OT), and B) high-affinity specific radioiodinated ligands for AVP and OT receptor sub-types; for use as pharmacological tools, and as potential therapeutic-agents.
The specific aims for the coming award period are 1. to enhance the potency and selectivity of our most promising antagonists for the following receptor sub-types: (i) AVP antidiuretic (V2); (ii) AVP vascular (V1a); (iii) AVP pituitary (V1b), and (iv) oxytocin uterine (OT). 2. To design AVP V2 antagonists which are effective in humans. 3. To design selective cyclic and linear AVP and OT agonists. 4. To improve the oral bioavailability of lead antagonists for each receptor sub-type. 5. To design potent and selective radioiodinated ligands for (i) AVP V2 receptors, (ii) AVP Vlb receptors, and for (iii) human OT uterine receptor. 6. To continue to supply, at no cost, other investigators with peptide agonists, antagonists and radioiodinated ligand precursors for use as pharmacological tools in their own independent studies. AVP V2 antagonists would be of therapeutic value for the treatment of the syndrome of inappropriate secretion of 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. AVP V1a antagonists may be useful in the treatment of some forms of hypertension. To meet goals 1-5, we will exploit promising cyclic and linear leads from the past award period using a combination of modern peptide design methods, including conformational restriction and molecular modelling and established SAR approaches. All peptides will be synthesized, purified and analyzed in the P.I.'s laboratory. In vitro and in vivo assays (an absolutely essential component of this project) will be carried out in the laboratory of Dr. W.Y. Chan, Cornell Univ. Med. Coll., N.Y. funds to support these assays are requested in this renewal. These bioassays had been carried out at no cost for over 20 years in the laboratory of the P.I.'s collaborator, Dr. Wilbur H. Sawyer. Assays for other collaborative studies with Dr. J.J. Dreifuss, Geneva, (Vlb receptor design), Dr. Claude Barberis, France, (with cell lines expressing human AVP V2 and human OT receptors; radioiodinated ligand design), Dr. Stefan Lundin, Sweden, (oral bioavailability), and Drs. Garland Marshall and Gregory Nikiforovich, St. Louis, (molecular modeling), will be at no cost to this project.
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