A VIP hybrid antagonist: from developmental neurobiology to clinical applications

Cell Mol Neurobiol. 1995 Dec;15(6):675-87. doi: 10.1007/BF02071131.

Abstract

1. The 28 amino acid vasoactive intestinal peptide, VIP, was originally isolated from the intestine, following a bioassay measuring vasodilating properties. Immunocytochemistry, receptor binding assays and in situ hybridizations have demonstrated VIP abundance in the nervous system, suggesting multiple bioactivities. 2. A pharmacological approach was chosen to dissect VIP activities and a prototype VIP antagonist (Met-Hybrid) consisting of a carboxyl fragment of VIP7-28 and a six amino acid fragment of neurotensin, neurotensin6-11-VIP7-28 was synthesized. 3. This hybrid peptide was designed to maintain the binding capacity of one parent molecule (VIP), while loosing the agonistic properties, representing a classical competitive receptor antagonist. Furthermore, the new molecule exhibited increased specificity to central nervous system VIP receptors. 4. The Met-Hybrid was originally discovered as a potent inhibitor of VIP function in vivo. In the adult rodent, acute administration of the antagonist resulted in blockade of VIP-mediated potentiation of sexual behavior and chronic intracerebroventricular application impaired VIP-associated learning abilities. During ontogeny, chronic injections of the molecule resulted in neuronal damage, disruption of the diurnal rhythmicity of motor behavior, and retardation in the acquisition of neonatal reflexes in the rat. 5. During gestation, severe microcephaly was induced by acute administration of the Met-Hybrid to pregnant mice. The hybrid antagonist inhibited VIP-stimulated mitosis in whole embryo cultures and in a variety of cancer cell lines in vitro and in vivo, suggesting therapeutical potential.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Brain / drug effects
  • Brain / embryology
  • Brain / physiology*
  • Cognition / drug effects
  • Humans
  • Molecular Sequence Data
  • Nervous System / drug effects
  • Nervous System Physiological Phenomena*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurotensin
  • Peptides / chemical synthesis
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Receptors, Vasoactive Intestinal Peptide / antagonists & inhibitors
  • Receptors, Vasoactive Intestinal Peptide / physiology*
  • Reflex / drug effects
  • Second Messenger Systems
  • Sexual Behavior, Animal / drug effects
  • Vasoactive Intestinal Peptide / antagonists & inhibitors*
  • Vasoactive Intestinal Peptide / physiology*

Substances

  • Peptides
  • Receptors, Vasoactive Intestinal Peptide
  • Vasoactive Intestinal Peptide
  • Neurotensin