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-<i>N</i>-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 <b>21</b>. Compared to NAN, compound <b>21</b> manifested overall improved pharmacological profiles. Follow-up hERG channel inhibition evaluation revealed a seven-fold decreased potency of compound <b>21</b> compared to NAN. Furthermore, several fundamental drug-like property evaluations suggested a reasonable ADME profile of <b>21</b>. Collectively, compound <b>21</b> appeared to be a promising opioid modulator for further development as a novel therapeutic agent toward opioid use disorder treatments.