Synthesis and in vitro evaluation of new potent antagonists of growth hormone-releasing hormone (GH-RH)

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-Arg(2) and Nle(27) modifications. Most analogs had Phe (pCl)(6) and Agm(29) substituents. The effect of other substitutions such as Abu(8) and/or Abu(15) and Ala(15) and various hydrophobic and hydrophilic D or L amino acids at position 8 were also investigated. Ail 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-Tyr(1), D-Arg(2)]hGH-RH (1-29)-NH2. Some antagonists were long acting. Among the peptides synthesized, antagonist PhAc-[D-Arg(2), Phe (pCl)(6), Abu(15), Nle(27)]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. (C) 1997 Elsevier Science Inc.