高等学校化学学报2026，Vol.47Issue(2)：47-58,12.DOI:10.7503/cjcu20250257
基于CVL-231的环丁胺类M4正向变构调节剂的设计、合成与活性
Design,Synthesis and Activity of Cyclobutylamine M4 Positive Allosteric Modulator Based on CVL-231
摘要
Abstract
Using the preclinical drug CVL-231 as a lead compound and introducing the 2-trifluoromethylpyridine moiety from the high-activity compound VU6000918,27 novel 2-trifluoromethylpyridine cyclobutylamide derivatives were designed and synthesized by modifying the heterocyclic moiety.The allosteric modulatory activity of the compounds on M4 receptor cells was assessed using the FLIPR fluorescence detection technique.The results revealed that several compounds exhibited significant cellular activity,especially for compounds Ⅳ1,Ⅳ12,Ⅳ20,Ⅳ23,Ⅳ25,Ⅳ26,and Ⅳ27.The results of the EC50 determination indicated that compound Ⅳ23 had an EC50 value as low as 979 nmol/L,which is slightly higher than that of the positive control VU0467154.Structure-activity relationship(SAR)analysis revealed that the introduction of a quinoline ring,particularly the 4-methylquinoline moiety,signifi-cantly enhanced the activity of the compounds.Molecular-docking simulations revealed that compound Ⅳ23 forms both hydrogen-bond and π-π stacking interactions with the M4 receptor protein(7TRP),providing a plausible mechanistic for its recognition by the target protein.In summary,compound IV23,as a promising lead compound for M4 positive allosteric modulators,provides an important research basis for subsequent structural optimization and drug development.关键词
M4正向变构调节剂/三氟甲基吡啶/环丁胺/合成/分子对接Key words
M4 positive allosteric modulator/Trifluoromethylpyridine/Cyclobutylamine/Synthesis/Molecular docking分类
化学化工引用本文复制引用
李馥莼,李文歆,何姝芳,陈毅昆,周皓,周海峰,刘祈星,田峦鸢..基于CVL-231的环丁胺类M4正向变构调节剂的设计、合成与活性[J].高等学校化学学报,2026,47(2):47-58,12.基金项目
国家自然科学基金(批准号:22278244)和宜昌人福药业有限责任公司研发项目(批准号:SDHZ2023029)资助. Supported by the National Natural Science Foundation of China(No.22278244)and the Research Fund from Yichang Humanwell Pharmaceutical Co.,Ltd.,China(No.SDHZ2023029). （批准号:22278244）
