In the search of 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 oncological applications.
- GH-RH antagonists
- GH-RH receptor binding
- Inhibitory activity of growth hormone-releasing hormone analogs (GH- RH)
- Structure-activity relationships
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience