Li Jinglan, Nishimura Hirokazu, Matsushima Ayami, Shimohigashi Yasuyuki
Laboratory of Structure–Function Biochemistry, Department of Chemistry, Faculty and Graduate School of Sciences, and Risk Science Research Center, Kyushu University, Fukuoka 812-8581, Japan.
Bioorg Med Chem. 2014 Nov 1;22(21):5721-6. doi: 10.1016/j.bmc.2014.09.049.
Antagonists of the neuropeptide nociceptin are expected to be potential analgesic and antineuropathic drugs acting on ORL1 GPCR receptors. The peptide library-based antagonist Ac-RYYRIK-NH2 inhibits the nociceptin activity mediated through ORL1, but preserves a considerably high level of agonist activity. We previously reported that the N-terminal acyl group is important for interaction with specific receptors, and developed isovarelyl-RYYRIK-NH2, which exhibits strong antagonist activity with negligible agonist activity. In the present study, in order to obtain a more potent antagonist, we further modified the isovarelyl group by replacing its Cβ atom with an oxygen, nitrogen, or sulfur atom to give the methyl group improved interaction ability. The methyl group bound to such heteroatoms was expected to enhance the hydrophobic interaction between the peptide and the ORL1 receptor. The RYYRIK-NH2 peptide with a methylthioacetyl group, CH3SCH2CO, revealed a higher receptor-binding affinity with strong antagonist activity, and the results suggested the presence of a receptor aromatic group as a complementary residue of this CH3S group.
神经肽孤啡肽的拮抗剂有望成为作用于ORL1 G蛋白偶联受体的潜在镇痛药和抗神经病药物。基于肽库的拮抗剂Ac-RYYRIK-NH2可抑制通过ORL1介导的孤啡肽活性，但仍保留相当高水平的激动剂活性。我们之前报道过，N端酰基对于与特定受体的相互作用很重要，并开发了异缬氨酰-RYYRIK-NH2，其表现出强大的拮抗剂活性，而激动剂活性可忽略不计。在本研究中，为了获得更强效的拮抗剂，我们通过将异缬氨酰基的Cβ原子替换为氧、氮或硫原子来进一步修饰该基团，以使甲基具有更强的相互作用能力。与这些杂原子相连的甲基有望增强肽与ORL1受体之间的疏水相互作用。带有甲硫乙酰基（CH3SCH2CO）的RYYRIK-NH2肽显示出更高的受体结合亲和力和强大的拮抗剂活性，结果表明存在一个受体芳香基团作为该CH3S基团的互补残基。
