Structure–Activity Relationship of N‑Cyclopropylmethyl-7α‑[para-(arylcarboxamido)phenyl]-6,14-endoethano-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 N-cyclopropylmethyl-7α-[para-(arylcarboxamido)phenyl]-6,14-endoethano-tetrahydronorthebaines. Several highly selective and potent KOR agonists have been identified. Notably, compound 5i 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 5i is a promising candidate for further studies.