Structure-Activity Relationship of -Cyclopropylmethyl-7α-[-(arylcarboxamido)phenyl]-6,14-ethano-tetrahydronorthebaines as Potent and Selective Kappa Opioid Receptor Agonists.

Research on KOR agonists with reduced central nervous system side effects represents a significant area in analgesic studies. Herein, a structure-activity relationship analysis was performed for a series of -cyclopropylmethyl-7α-[-(arylcarboxamido)phenyl]-6,14-ethano-tetrahydronorthebaines. Several highly selective and potent KOR agonists have been identified. Notably, compound exhibited a subpicomolar binding affinity for KOR and exceptional subtype selectivity over MOR and DOR, consistent with its in vitro functional activities. It was identified as a G protein-biased KOR agonist, and its molecular interactions with KOR were elucidated. Additionally, this compound exhibited potent, dose-dependent, long-lasting, and KOR-mediated antinociceptive activity in both hot plate and abdominal constriction assays. It did not display any noticeable aversion or sedation in rodent models. These pharmacological characteristics suggest that compound is a promising candidate for further studies.