Kオピオイド受容体とモルフィナン骨格を保有するリガンドの化学相互作用の振動分光研究

• Published in: 日本薬理学会年会要旨集 p. 1-B-SS03-5
• Main Authors: 小林, 拓也, 神取, 秀樹, 岩田, 聖矢, 寿野, 良二, 寿野, 千代, 西川, 遼, 片山, 耕大
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2023
• Subjects: opioid; opioid receptor
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.97.0_1-B-SS03-5

Opioid receptors (ORs) belong to a member of GPCRs and are receptive to compounds that exert analgesic effects, such as morphine. Many opioid ligands contain a morphinan structure, and their pharmacological activity (efficacy) varies, including agonists and antagonists. It is important in drug discovery to elucidate the binding mechanism of ligands to ORs and the relationship between their efficacy. Here, we applied vibrational spectroscopy-based GPCR-ligand interaction studies to κ-opioid receptor (KOR) to elucidate differences in the binding mechanism of various ligands to the receptor, which share a common morphinan structure but exhibit different efficacy. The agonist binding spectra showed the spectral down-shift in amide-I band reflecting to weakening the hydrogen bond between C=O and N-H pairs of peptide backbone, whereas the antagonist bound spectra showed the opposite change, which indicates the different conformational changes that occur between an agonist and antagonist binding to KOR. Furthermore, differences in the vibrational bands derived from functional group of amino acids were also observed for different ligand efficacy. The mechanism by which differences in pharmacological efficacy arise from a common morphinan structure will be discussed, based on protein backbone and functional group of amino acid changes.