Superactive lipophilic peptides discriminate multiple vasoactive intestinal peptide receptors
Gozes, I.; Lilling, G.; Glazer, R.; Ticher, A.; Ashkenazi, I.E.; Davidson, A.; Rubinraut, S.; Fridkin, M.; Brenneman, D.E.
Journal of Pharmacology and Experimental Therapeutics 273(1): 161-167
1995
ISSN/ISBN: 0022-3565 PMID: 7714762 Document Number: 453216
To distinguish vasoactive intestinal peptide (VIP) receptors in the brain-mediating neurotransmission and neurotrophism, potent VIP analogues were designed. Using a single amino acid substitution and the addition of a fatty acyl moiety, an analogue was devised that exhibited both a 100-fold greater potency than VIP and specificity for a VIP receptor associated with neuronal survival. This VIP agonist increased neuronal survival via a cAMP-independent mechanism. Identical chemical modification of a prototype VIP antagonist (Met-Hybrid, Neurotensin-6-11-VIP-7-28) also resulted in a 100-fold greater potency in blocking VIP-mediated increases in neuronal survival. Blockade of circadian activity rhythms was limited to VIP antagonists that could inhibit VIP-mediated increases in cAMP. These lipophilic peptides provide novel tools in receptor discrimination and drug design.