title: Designed modification of partial agonist of ORL1 nociceptin receptor for conversion into highly potent antagonist.
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-NH(2) 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-NH(2), where acyl (R-CO) possesses a series of alkyl groups, R=C(n)H(2n+1) (n=0-5). The isovaleryl derivative with the C(4)H(9) (=(CH(3))(2)CHCH(2)-) 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-NH(2) and producing pure antagonist activity.
authors: Laboratory of Structure-Function Biochemistry, Department of Chemistry, Research-Education Centre of Risk Science, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
authors: Jinglan
authors: J
authors: Li
authors: Kaname
authors: K
authors: Isozaki
authors: Kazushi
authors: K
authors: Okada
authors: Ayami
authors: A
authors: Matsushima
authors: Takeru
authors: T
authors: Nose
authors: Tommaso
authors: T
authors: Costa
authors: Yasuyuki
authors: Y
authors: Shimohigashi
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009292:Narcotic Antagonists; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D009292:Narcotic Antagonists; D010455:Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor