Synthesis and Biological Evaluation in Vitro of Selective, High Affinity Peptide Antagonists of Human Melanin-Concentrating Hormone Action at Human Melanin-Concentrating Hormone Receptor 1

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• 作者：Maria A. Bednarek ; Donna L. Hreniuk ; Carina Tan ; Oksana C. Palyha ; Douglas J. MacNeil ; Lex H. Y. Van der Ploeg ; Andrew D. Howard ; and Scott D. Feighner
• 刊名：Biochemistry
• 出版年：2002
• 出版时间：May 21, 2002
• 年：2002
• 卷：41
• 期：20
• 页码：6383 - 6390
• 全文大小：75K
• 年卷期：v.41,no.20(May 21, 2002)
• ISSN：1520-4995

文摘

Human melanin-concentrating hormone (hMCH) and many of its analogues are potent butnonspecific ligands for human melanin-concentrating hormone receptors 1 and 2 (hMCH-1R and hMCH-2R). To differentiate between the physiological functions of these receptors, selective antagonists areneeded. In this study, analogues of Ac-Arg⁶-cyclo(S-S)(Cys⁷-Met⁸-Leu⁹-Gly¹⁰-Arg¹¹-Val¹²-Tyr¹³-Arg¹⁴-Pro¹⁵-Cys¹⁶)-NH₂, a high affinity but nonselective agonist at hMCH-1R and hMCH-2R, were preparedand tested in binding and functional assays on cells expressing these receptors. In the new analogues,5-aminovaleric acid (Ava) was incorporated in place of the Leu⁹-Gly¹⁰ and/or Arg¹⁴-Pro¹⁵ segments ofthe disulfide ring. Several of these compounds turned out to be high affinity antagonists selective forhMCH-1R. Moreover, even at micromolar concentrations, they were devoid of agonist potency at bothhMCH receptors and not effective as hMCH-2R antagonists. For example, peptide 14, Gva⁶- cyclo(S-S)(Cys⁷-Met⁸-Leu⁹-Gly¹⁰-Arg¹¹-Val¹²-Tyr¹³-Ava^14,15-Cys¹⁶)-NH₂, (Gva = 5-guanidinovaleric acid), wasa full competitive hMCH-1R antagonist (IC₅₀ = 14 nM, K_B = 0.9 nM) with more than 1000-fold selectivityover hMCH-2R. Examination of various compounds with Ava in positions 9,10 and/or 14,15 revealedthat the Leu⁹-Gly¹⁰ and Arg¹⁴-Pro¹⁵ segments of the disulfide ring are the principal structural elementsdetermining hMCH-1R selectivity and ability to act as a hMCH-1R antagonist.