Endocrinology, Vol 117, 1759-1764, Copyright © 1985 by Endocrine Society

ARTICLES

Structural requirements for the activation of rat anterior pituitary adenylate cyclase by growth hormone-releasing factor (GRF): discovery of (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2 as a GRF antagonist on membranes

P Robberecht, DH Coy, M Waelbroeck, ML Heiman, P de Neef, JC Camus and J Christophe

The efficacy and potency of 14 GH-releasing factor (GRF) analogs, substituted in position 1 to 7, on adenylate cyclase activation in crude homogenates from rat anterior pituitary were related to those of human pancreatic GRF(1-29)-amide and vasoactive intestinal peptide. Among several D-amino acid substitutions, that in position 2 was the only one to yield a super-agonist [with a Kact (concentration required for half-maximal adenylate cyclase activation) 2 times lower than that of GRF(1-29)-NH2]. By contrast, D-isomer substitution in position 1 and 3 was without effect and D-isomer substitution in position 4, 6, or 7 decreased the affinity of the analog. The N-acetylated analog of GRF was as potent and active as the parent peptide, and the identity of the amino acid in position 2 of (N-Ac-Tyr1)-GRF(1-29)-NH2 proved to be determining for enzyme activation, with D-Phe2 and D-Trp2 derivatives acting as partial agonists and the (N-Ac-Tyr1,D-Arg2) analog being an efficient competitive antagonist of GRF(1-29)-NH2. With use of this antagonist, it was possible to demonstrate that GRF and vasoactive intestinal peptide receptors represent distinct entities in the rat anterior pituitary.

This article has been cited by other articles:

				M. Zarandi, J. L. Varga, A. V. Schally, J. E. Horvath, G. L. Toller, M. Kovacs, M. Letsch, K. Groot, P. Armatis, and G. Halmos Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities PNAS, March 21, 2006; 103(12): 4610 - 4615. [Abstract] [Full Text] [PDF]

				J. L. Varga, A. V. Schally, J. E. Horvath, M. Kovacs, G. Halmos, K. Groot, G. L. Toller, Z. Rekasi, and M. Zarandi Increased activity of antagonists of growth hormone-releasing hormone substituted at positions 8, 9, and 10 PNAS, February 10, 2004; 101(6): 1708 - 1713. [Abstract] [Full Text] [PDF]

				K. E. Mayo, L. J. Miller, D. Bataille, S. Dalle, B. Goke, B. Thorens, and D. J. Drucker International Union of Pharmacology. XXXV. The Glucagon Receptor Family Pharmacol. Rev., March 1, 2003; 55(1): 167 - 194. [Abstract] [Full Text] [PDF]

				Z. Rekasi, J. L. Varga, A. V. Schally, G. Halmos, K. Groot, and T. Czompoly Antagonistic actions of analogs related to growth hormone-releasing hormone (GHRH) on receptors for GHRH and vasoactive intestinal peptide on rat pituitary and pineal cells in vitro PNAS, February 1, 2000; 97(3): 1218 - 1223. [Abstract] [Full Text] [PDF]

				J. L. Varga, A. V. Schally, V. J. Csernus, M. Zarandi, G. Halmos, K. Groot, and Z. Rekasi Synthesis and biological evaluation of antagonists of growth hormone-releasing hormone with high and protracted in vivo activities PNAS, January 19, 1999; 96(2): 692 - 697. [Abstract] [Full Text] [PDF]