Inhibition of GH release of rats by new potent antagonists of growth hormone-releasing hormone (GH-RH).

Biological activity of a new series of potent GH-RH antagonists containing formyl or phenylacetyl group at the N-terminus of the sequence [D-Arg2,Phe(4-Cl)6,Nle27]hGH-RH(1-29)NH2, as well as various substitutions in positions 8, 15, or 28, and in some cases Agm in position 29, was evaluated in vivo. All five antagonists, administered at a 27-fold molar excess to rats, suppressed the GH-releasing effect of exogenous GH-RH(1-29)-NH2 by 64-75%. The inhibitory effects lasted for more than 15 min. The most potent analogue, PhAc-[D-Arg2,Phe(4-Cl)6,Abu15,Nle27]hGH-RH(1-28)Agm (MZ-5-156), showed an in vivo potency 7-16 times higher than the early antagonist [Ac-Tyr1,D-Arg2]hGH-RH(1-29)-NH2, which was used as standard. MZ-5-156 was capable of decreasing serum GH levels after intravenous, intraperitoneal, or intramuscular administration. In vitro, in the superfused rat pituitary cell system, MZ-5-156 induced a prolonged inhibition of GH release after continuous long-term administration and showed a potency more than 100 times greater than the standard antagonist. These results show that N-terminal acylation with phenylacetic acid of the sequence [D-Arg2,Phe(4-Cl)6,Nle27]hGH-RH(1-29)-NH2, containing modifications in positions 8, 15, 28, or 29, results in antagonists with high and protracted potency both in vivo and in vitro. In view of high antagonistic activity and prolonged duration of action, some of these antagonists of GH-RH may find clinical application for the treatment of IGF-dependent cancers.