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 journal › Article

5 Citations (Scopus)

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

Fingerprint

Sermorelin
Growth Hormone-Releasing Hormone
Human Growth Hormone
Rats
Substitution reactions
Peptides

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity. / Toth, Katalin; Kovacs, Magdolna; Zarandi, Marta; Halmos, Gabor; Groot, Kate; Nagy, Attila; Kele, Zoltan; Schally, Andrew V.

In: Journal of Peptide Research, Vol. 51, No. 2, 12.03.1998, p. 134-141.

Research output: Contribution to journal › Article

Toth, K, Kovacs, M, Zarandi, M, Halmos, G, Groot, K, Nagy, A, Kele, Z & Schally, AV 1998, 'New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity', Journal of Peptide Research, vol. 51, no. 2, pp. 134-141.
Toth K, Kovacs M, Zarandi M, Halmos G, Groot K, Nagy A et al. New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity. Journal of Peptide Research. 1998 Mar 12;51(2):134-141.
Toth, Katalin ; Kovacs, Magdolna ; Zarandi, Marta ; Halmos, Gabor ; Groot, Kate ; Nagy, Attila ; Kele, Zoltan ; Schally, Andrew V. / New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity. In: Journal of Peptide Research. 1998 ; Vol. 51, No. 2. pp. 134-141.
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AU - Toth, Katalin

AU - Kovacs, Magdolna

AU - Zarandi, Marta

AU - Halmos, Gabor

AU - Groot, Kate

AU - Nagy, Attila

AU - Kele, Zoltan

AU - Schally, Andrew V

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N2 - 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.

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