期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 16, 期 5, 页码 2635-2644出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2007.11.043
关键词
acyl group; antagonist; nociceptin; structure-activity relationships
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)(2)CHCH2-) 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. (C) 2007 Elsevier Ltd. All rights reserved.
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