Li Jinglan, Isozaki Kaname, Okada Kazushi, Matsushima Ayami, Nose Takeru, Costa Tommaso, Shimohigashi Yasuyuki
Laboratory of Structure-Function Biochemistry, Department of Chemistry, Research-Education Centre of Risk Science, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
Bioorg Med Chem. 2008 Mar 1;16(5):2635-44. doi: 10.1016/j.bmc.2007.11.043. Epub 2007 Nov 21.
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.
孤啡肽是阿片受体样1（ORL1）受体的内源性激动剂配体，其拮抗剂是镇痛和抗神经病变药物治疗的潜在靶点。Ac-RYYRIK-NH₂是从肽库中分离出的一种六肽拮抗剂，可抑制通过ORL1介导的孤啡肽活性。然而，这种拮抗剂活性所需的结构元件仍不确定。在本研究中，我们评估了乙酰甲基在受体结合和激活中的重要性，研究了肽酰-RYYRIK-NH₂，其中酰基（R-CO）具有一系列烷基，R = C(n)H(2n+1)（n = 0-5）。发现具有C₄H₉（=(CH₃)₂CHCH₂-）基团的异戊酰衍生物具有高受体结合亲和力和强拮抗性质。该肽实现了消除Ac-RYYRIK-NH₂激动剂活性并产生纯拮抗剂活性的主要目标。
