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

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2635-2644
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number5
DOIs
Publication statusPublished - Mar 1 2008

All Science Journal Classification (ASJC) codes

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

Fingerprint Dive into the research topics of 'Designed modification of partial agonist of ORL1 nociceptin receptor for conversion into highly potent antagonist'. Together they form a unique fingerprint.

  • Cite this