Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 E Leigh Street, Richmond, Virginia23298, United States.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia23298, United States.
J Med Chem. 2023 Jan 12;66(1):577-595. doi: 10.1021/acs.jmedchem.2c01499. Epub 2022 Dec 20.
The search for selective opioid ligands with desired pharmacological potency and improved safety profile has always been an area of interest. Our previous effort yielded a potent opioid modulator, NAN, a 6α--7'-indolyl-substituted naltrexamine derivative, which exhibited promising pharmacological activities both in vitro and in vivo. However, significant human ether-a-go-go-related gene (hERG) liability limited its further development. Therefore, a systematic structural modification on NAN was conducted in order to alleviate hERG toxicity while preserving pharmacological properties, which led to the discovery of 2'-methylindolyl derivative compound . Compared to NAN, compound manifested overall improved pharmacological profiles. Follow-up hERG channel inhibition evaluation revealed a seven-fold decreased potency of compound compared to NAN. Furthermore, several fundamental drug-like property evaluations suggested a reasonable ADME profile of . Collectively, compound appeared to be a promising opioid modulator for further development as a novel therapeutic agent toward opioid use disorder treatments.
寻找具有理想药理效力和改善安全性的选择性阿片类配体一直是研究的热点。我们之前的研究成果得到了一种强效的阿片类调节剂 NAN，它是一种 6α--7'-吲哚基取代的纳曲胺衍生物，在体外和体内均表现出有前景的药理学活性。然而，其显著的人 Ether-a-go-go 相关基因 (hERG) 毒性限制了其进一步的发展。因此，我们对 NAN 进行了系统的结构修饰，以减轻 hERG 毒性的同时保留药理学特性，从而发现了 2'-甲基吲哚基衍生物化合物 。与 NAN 相比，化合物 表现出整体改善的药理学特征。后续的 hERG 通道抑制评估显示，化合物 的效力比 NAN 降低了七倍。此外，几项基本的药物样性质评估表明 具有合理的 ADME 特征。总的来说，化合物 似乎是一种有前途的阿片类调节剂，可进一步开发为治疗阿片类药物使用障碍的新型治疗药物。
