New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity

Katalin Toth, Magdolna Kovacs, Marta Zarandi, Gabor Halmos, Kate Groot, Attila Nagy, Zoltan Kele, Andrew V. Schally

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Based on our previous results, in conjunction with various structural considerations, 19 new analogs of the GHRH antagonist [PhAc-Tyr1,D- Arg2,Phe(pCl)6,Abu15,Nle27,Agm29]hGHRH(1-29) (MZ-5-156) were synthesized by the solid-phase method. These compounds were designed to develop further analogs of this class with increased receptor-binding affinity. All analogs had Abu15 and Nle27 modifications and were acylated with phenylacetic acid at the N-terminus. Most of the analogs had D-Arg2 and Phe(pCl)6 substituents and Agm29 or Arg29-NH2 at the C-terminus. Additional single substitutions consisted of the incorporation of D- or L- Tic1, D-Tic2, Tic6 or Phe(pNO2)6 and Arg29-NH2. The Arg29-NH2 analog of MZ-5-156 (KT-48) was further modified by single substitutions using Pal1; D-Tpi2; D- or L-Phe4; Phe(pX)6 X = F, Cl, I; Tyr7; Aib8; Tyr(Me)10 or Phe(pCl)10. Four peptides had multiple substitutions. All the analogs were evaluated for their ability to inhibit GH release induced by hGHRH(1-29)NH2 in vitro and some were also tested in vivo. Peptides [PhAc- Tyr1,D-Arg2,Phe(pI)6,Abu15,Nle27]hGHRH(1-29)NH2 (KT-30), [PhAc- Tyr1,D-Arg2,Phe(pCl)6,Aib8,Abu15,Nle27]hGHRH(1-29)NH2 (KT-50) and [PhAc-Tyr1,D-Arg2,Phe(pCl)6,Tyr(Me)10,Abu15,Nle27]hGHRH(1-29)NH2 (KT-40) with Phe(pI)6, Aib8 or Tyr(Me)10 modifications, respectively, showed high and prolonged inhibitory effect in superfused rat pituitary system. Analog KT-50 also exhibited a strong and long-term inhibitory activity in vivo in rats. Most of the new analogs showed high binding affinities to rat pituitary GHRH receptors.

Original languageEnglish (US)
Pages (from-to)134-141
Number of pages8
JournalJournal of Peptide Research
Volume51
Issue number2
StatePublished - Mar 12 1998
Externally publishedYes

Keywords

  • Antagonistic activity
  • GHRH antagonists
  • GHRH receptor binding
  • Peptides

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

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    Toth, K., Kovacs, M., Zarandi, M., Halmos, G., Groot, K., Nagy, A., Kele, Z., & Schally, A. V. (1998). New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity. Journal of Peptide Research, 51(2), 134-141.