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-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 Ala15 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.
Zarandi
M
M
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70146, USA.
Kovacs
M
M
Horvath
J E
JE
Toth
K
K
Halmos
G
G
Groot
K
K
Nagy
A
A
Kele
Z
Z
Schally
A V
AV
D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D013006:Growth Hormone / Q000097:blood / Q000737:chemistry; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000378:metabolism / Q000494:pharmacology; D051381:Rats
D011500:Protein Synthesis Inhibitors; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone