VIP FAMILY PEPTIDES-ANALOGS-GH, INSULIN, GLUCAGON

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Vasoactive intestinal peptide (VIP), secretin, glucagon, gastric inhibitory peptide (GIP) and, most recently, PHI and growth hormone releasing factor (GRF) are members of a family of peptides which are known to control numerous GI, pancreatic, and endocrine events. Despite their diverse biological activities, considerable sequence homology exists between each peptide thus creating a unique opportunity of efficient (i.e. worthwhile modifications to one peptide might be reasonably expected to be directly applicable to a comparable sequence region of another) structure-activity studies aimed at elucidating mechanisms of action, increasing activities, developing short, conformationally restricted analogues, increasing selectivities, and developing competitive antagonists. Such extensive SAR studies on peptides of this size (ca.30 residues) have been made possible by our development over a seven year period of rapid solid-phase syntheses and HPLC purification techniques for each of these peptides. Analogues prepared similarly have already yielded more active forms of glucagon and GRF and competitive antagonists of VIP and GRF. Analogues of these peptides can be expected to have therapeutic significance in many areas, notably diabetes mellitus through the elucidation of new mechanisms governing the control of insulin and glucagon levels and glucagon and GRF antagonist, ulcers through secretin effect on bicarbonate release, certain lung disorders through VIP-stimulated bronchodilation, and growth stimulation in cases of hypothalamic GRF deficiencies. Furthermore, competitive antagonists of all of these peptides, as well as having clinical potentials in some instances, would be of great value in elucidating mechanisms of action of endogenous peptides. Assay methods to be used in this research include effects on GH, prolactin, insulin, and glucagon release in the rat, GH and prolactin release from monolayer pituitary cell cultures, and in vitro effects on adenylate cyclase activity in may tissue types. These latter studies are in collaboration with Dr. Jean Christophe. Other formal collaborations for evaluation of present and future VIP antagonists with various investigators and 500 mhz NMR studies with Professor Van Binst in Brussels have been established.