Structural Alterations of the "Address" Moiety of NAN Leading to the Discovery of a Novel Opioid Receptor Modulator with Reduced hERG Toxicity.

ABSTRACT: 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-N-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 21. Compared to NAN, compound 21 manifested overall improved pharmacological profiles. Follow-up hERG channel inhibition

SUBMITTER: Ma H 

PROVIDER: S-EPMC10546487 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature