Synthesis and biological evaluation of antagonists of growth hormone-releasing hormone with high and protracted in vivo activities

摘要: Some antagonists of human growth hormone-releasing hormone (hGH-RH) synthesized previously were shown to inhibit in vivo proliferation various cancers nude mice. However, the activity these analogs requires an increase assure clinical efficacy. In attempt prepare hGH-RH with a high and protracted activity, we biologically tested 22 antagonistic hGH-RH(1-29)NH2. The ability hGH-RH-induced GH release was evaluated vitro superfused rat pituitary system, as well after i.v. injection into rats. binding affinity peptides GH-RH receptors also determined. All had common core sequence [PhAc-Tyr1,D-Arg2, Phe(4-Cl)6 (para-chlorophenylalanine), Abu15 (alpha-aminobutyric acid), Nle27]hGH-RH(1-29)NH2 contained Arg, D-Arg, homoarginine (Har), norleucine (Nle), other substitutions. following determined have and/or activity: [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Arg9,Abu15,Nle27, D-Arg29]hGH-RH(1-29)NH2 (JV-1-10), [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6, Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (MZ-6-55), [PhAc-Tyr1, D-Arg2,Phe(4-Cl)6,Arg9,Abu15,Nle27,D-Arg28,Har29 ]hGH-RH(1-29)NH2 (JV-1-36), [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Har9,Tyr(Me)10,Abu15, Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-38). Among tested, analog JV-1-36 showed highest induced strong prolonged inhibition for at least 30 min. antagonist JV-1-38 slightly less potent than both but proved be very long-acting vivo, suppressing GH-RH-induced even 60 High activities indicate improvement over earlier analogs. could find applications treatment dependent on insulin-like factors I II.