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

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
evaluation revealed a seven-fold decreased potency of compound 21 compared to NAN. Furthermore, several fundamental drug-like
property evaluations suggested a reasonable ADME profile of 21. Collectively, compound 21 appeared to be
a promising opioid modulator for further development as a novel therapeutic
agent toward opioid use disorder treatments.