New antagonists of LHRH II. Inhibition and potentiation of LHRH by closely related analogues

SANDOR BAJUSZ, VALER J. CSERNUS, TAMAS JANAKY, LAZARO BOKSER, MATYAS FEKETE, ANDREW V. SCHALLY

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

Modifications of the previously described LHRH antagonists, [Ac-D-Na1(2)1, D-Phe(4Cl)2, D-Trp3, D-Cit6, D-Ala10]LHRH and the corresponding D-Hci6 analogue, have been made to alter the hydrophobicity of the N-terminal acetyl-tripeptide portion. Substitution of D-Trp3 with the less hydrophobic D-Pa1(3) had only marginal effects on the antagonistic activities and receptor binding potencies of the D-Cit/D-Hci6 analogues, but it appeared to further improve the toxicity lowering effect of D-Cit/D-Hci6 substitution. Antagonists containing D-Pa1(3)3 and D-Cit/D-Hci6 residues, i.e. [Ac-D-Na1(2)1, D-Phe(4Cl)2, D-Pa1(3)3, D-Cit6, D-Ala10]LHRH (SB-75) and [Ac-D-Na1(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Hci6, D-Ala10]LHRH (SB-88), were completely free of the toxic effects, such as cyanosis and respiratory depression leading to death, which have been observed in rats with the D-Trp3, D-Arg6 antagonist and related antagonists. Replacement of the N-acetyl group with the hydrophilic carbamoyl group caused a slight decrease in antagonistic activities, particularly in vitro. Introduction of urethane type acyl group such as methoxycarbonyl (Moc) or t-butoxycarbonyl (Boc) led to analogues that showed LHRH-potentiating effect. The increase in potency induced by these analogues, e.g. [Moc-D-Na1(2)1, D-Phe(4Cl)2, D-Trp3, D-Cit6, D-Ala10]LHRH and [Boc-D-Phe1, D-Phe(4Cl)2, D-Pa1(3)3, D-Cit6, D-Ala10]LHRH, was 170-260% and persisted for more than 2 h when studied in a superfused rat pituitary system.

Original languageEnglish (US)
Pages (from-to)425-435
Number of pages11
JournalInternational journal of peptide and protein research
Volume32
Issue number6
DOIs
StatePublished - Dec 1988
Externally publishedYes

Keywords

  • LHRH analogues
  • antiovulatory activity of LHRH analogues
  • inhibition of LHRH
  • potentiation of LHRH
  • receptor binding of LHRH analogues
  • toxicity of LHRH analogues

ASJC Scopus subject areas

  • Biochemistry

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