Design, synthesis, and biological activities of a potent and selective α‐melanotropin antagonist

FAHAD AL‐OBEIDI, VICTOR J. HRUBY, MAC E. HADLEY, TOMI K. SAWYER, ANA M. DEL CASTRUCCI

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Based on structure‐activity relationships of the potent α‐MSH agonist, Ac‐Nle4‐Asp5‐His6‐d‐Phe7‐Arg8‐Trp9‐Lys10‐NH2, several analogs of the general formula Ac‐Nle4‐Asp5‐Waa6‐Xaa7‐Yaa8‐Zaa9‐Lys10‐NH2 were synthesized and tested on frog and lizard skin bioassays for their possible inhibitory actions against α‐MSH on melanocyte stimulation. When Waa6= Trp, Xaa7= D‐Phe, Yaa8= Nle and Zaa = Trp, a highly potent α‐MSH antagonist, Ac‐Nle‐Asp‐Trp‐d‐Phe‐Nle‐Trp‐Lys‐NH., with selectivity on the frog skin α‐MSH receptor system (PA2= 8.4) was obtained. However, several modifications in the amino acid sequence of the peptide resulted in a complete loss of antagonistic activity and a recovery of very weak agonistic action. The following changes in the amino acid sequence of the peptide were examined; His or d‐Trp for Waa, l‐Phe for Xaa, Arg, Ala or Pro for Yaa, and d‐TV for Zaa. All resulted in full agonists with no antagonistic activity. In addition, lactam cyclization between the Asp5 and Lys10 side chains in the antagonist gave a full agonist and a complete loss of antagonistic activity. Efforts to develop a rational approach for the design of selective α‐MSH antagonists for the frog skin α‐MSH receptor will be discussed.

Original languageEnglish (US)
Pages (from-to)228-234
Number of pages7
JournalInternational journal of peptide and protein research
Volume35
Issue number3
DOIs
StatePublished - Mar 1990

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Keywords

  • MSH antagonist
  • antagonist
  • melanocyte
  • melanocyte stimulating hormone (MSH)
  • melanotropin

ASJC Scopus subject areas

  • Biochemistry

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