Wei Li

The κ-opioid receptor (KOR) is recognized as a promising therapeutic target for the development of nonaddictive analgesics. However, the clinical utility of typical KOR agonists is limited by central adverse effects. SLL-022CCP is a novel KOR-selective ligand derived from a northebaine-based 4,5-epoxymorphinan scaffold, and we have previously demonstrated its high binding affinity for KOR. In this study, we performed a systematic evaluation of SLL-022CCP through in vitro and in vivo assays. In vitro, SLL-022CCP acted as an extremely potent full agonist at the KOR, inhibiting cAMP production with an EC₅₀ of 0.002 nM, and exhibited high receptor subtype selectivity over the μ-opioid receptor (MOR, EC₅₀ = 1.6 nM) and δ-opioid receptor (DOR, EC₅₀ = 30.0 nM). SLL-022CCP recruited β-arrestin at the KOR with an EC₅₀ of 15.5 nM and at the MOR with an EC₅₀ of 668.0 nM. Molecular docking data for SLL-022CCP revealed that it maintains canonical interactions with the KOR orthosteric site while extending its terminal phenyl moiety into a hydrophobic subpocket. In vivo, SLL-022CCP produced potent antinociception in the hot plate test (ED₅₀ = 1.816 mg/kg), acetic acid-induced writhing test (ED₅₀ = 0.113 mg/kg), and significant antipruritic effects in the histamine-induced itch test (ED₅₀ = 0.079 mg/kg) and CFA-induced itch test (ED₅₀ = 0.105 mg/kg). The antinociceptive effects of SLL-022CCP were antagonized by the KOR-selective antagonist Nor-BNI, but not by the MOR antagonist CTAP (1 mg/kg, i.p.), supporting primarily KOR-mediated activity. Importantly, at the antinociceptive dose, SLL-022CCP did not elicit significant motor incoordination or conditioned place aversion (CPA) under current experimental conditions, while eliciting transient sedation, distinguishing it from the typical arylacetamide derivatives, like U50,488H. Collectively, these results identify SLL-022CCP as a highly potent and selective KOR agonist with a unique pharmacological profile that exhibits robust antinociceptive and antipruritic effects with low central side effects.

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.