Designed modification of partial agonist of ORL1 nociceptin receptor for conversion into highly potent antagonist

Jinglan Li, Kaname Isozaki, Kazushi Okada, Ayami Matsushima, Takeru Nose, Tommaso Costa, Yasuyuki Shimohigashi

研究成果: Contribution to journalArticle

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Nociceptin is an endogenous agonist ligand of the ORL1 (opioid receptor-like 1) receptor, and its antagonist is a potential target of therapeutics for analgesic and antineuropathy drugs. Ac-RYYRIK-NH2 is a hexapeptide isolated from the peptide library as an antagonist that inhibits the nociceptin activities mediated through ORL1. However, the structural elements required for this antagonist activity are still indeterminate. In the present study, we evaluated the importance of the acetyl-methyl group in receptor binding and activation, examining the peptides acyl-RYYRIK-NH2, where acyl (R-CO) possesses a series of alkyl groups, R = CnH2n+1 (n = 0-5). The isovaleryl derivative with the C4H9 (=(CH3)2CHCH2-) group was found to reveal a high receptor-binding affinity and a strong antagonist nature. This peptide achieved a primary goal of eliminating the agonist activity of Ac-RYYRIK-NH2 and producing pure antagonist activity.

元の言語英語
ページ(範囲)2635-2644
ページ数10
ジャーナルBioorganic and Medicinal Chemistry
16
発行部数5
DOI
出版物ステータス出版済み - 3 1 2008

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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