A VIP HYBRID ANTAGONIST - FROM DEVELOPMENTAL NEUROBIOLOGY TO CLINICAL-APPLICATIONS

1. The 28 amino acid vasoactive intestinal peptide, VIP, was originall y isolated from the intestine, following a bioassay measuring vasodila ting properties, Immunocytochemistry, receptor binding assays and in s itu hybridizations have demonstrated VIP abundance in the nervous syst em, suggesting multiple bioactivities. 2. A pharmacological approach w as chosen to dissect VIP activities and a prototype VIP antagonist (Me t-Hybrid) consisting of a carboxyl fragment of VIP7-28 and a six amino acid fragment of neurotensin, neurotensin(6-11)-VIP7-28 was synthesiz ed. 3. This hybrid peptide was designed to maintain the binding capaci ty of one parent molecule (VIP), while loosing the agonistic propertie s, representing a classical competitive receptor antagonist, Furthermo re, the new molecule exhibited increased specificity to central nervou s system VIP receptors. 4. The Met-Hybrid was originally discovered as a potent inhibitor of VIP function in vivo. In the adult rodent, acut e administration of the antagonist resulted in blockade of VIP-mediate d potentiation of sexual behavior and chronic intracerebroventricular application impaired VIP-associated learning abilities. During ontogen y, chronic injections of the molecule resulted in neuronal damage, dis ruption of the diurnal rhythmicity of motor behavior, and retardation in the acquisition of neonatal reflexes in the rat. 5. During gestatio n, severe microcephaly was induced by acute administration of the Met- Hybrid to pregnant mice. The hybrid antagonist inhibited VIP-stimulate d mitosis in whole embryo cultures and in a variety of cancer cell lin es in vitro and in vivo, suggesting therapeutical potential.