Synthesis and In Vitro Evaluation of New Potent Antagonists of Growth Hormone-Releasing Hormone (GH-RH)

Abstract

Zarandi, M., M. Kovacs, J. E. Horvath, K. Toth, G. Halmos, K. Groot, A. Nagy, Z. Kele, and A. V. Schally, Synthesis and in vitro evaluation of new potent antagonists of growth hormone-releasing hormone (GH-RH). Peptides 18(3) 423–430, 1997.—In the search for more potent antagonists of hGH-RH, 20 new analogs were synthesized, purified and tested in vitro. All the analogs were based on the N-terminal sequence of 28 or 29 amino acid residues of hGH-RH, but contained D-Arg2 and Nle27 modifications. Most analogs had Phe (pCl)6 and Agm29 substituents. The effect of other substitutions such as Abu8 and/or Abu15 and Ala 15 and various hydrophobic and hydrophilic d or l amino acids at position 8 were also investigated. All the peptides were acylated at the N-terminus in an attempt to increase the antagonistic activity. In the superfused rat pituitary cell system, most analogs inhibited more powerfully the GH release induced by GH-RH than the standard antagonist [Ac-Tyr1, D-Arg2]hGH-RH (1-29)-NH2. Some antagonists were long acting. Among the peptides synthesized, antagonist PhAc-[D-Arg2, Phe (pCl)6, Abu15, Nle27] hGH-RH (1-28)Agm (MZ-5-156) appeared to be the most potent and inhibited GH release in vitro 63-200 times more powerfully than the standard antagonist. MZ-5-156 and other antagonists showed high binding affinities to membrane receptors for GH-RH. Some of these hGH-RH antagonists could be further developed for possible onocological applications.