Discovery of a highly selective and potent kappa opioid receptor agonist from N-cyclopropylmethyl-7α-piperazinyl -6,14-endoethano-tetrahydronorthebaines.

Kappa opioid receptor (KOR) agonists remain promising candidates for the development of antinociceptive and antipruritic therapeutics. Here, we report the design, synthesis, and biological evaluation of a series of N-cyclopropylmethyl-7α-piperazinyl-6,14-endoethano-tetrahydronorthebaines derived from the 4,5-epoxymorphinan scaffold. Several derivatives displayed subnanomolar to low-nanomolar KOR affinity together with pronounced subtype selectivity in radioligand binding assays. Among them, compound 10e exhibited exceptionally high KOR affinity (Ki = 1.6 pM) and more than 100-fold selectivity over μ- and δ-opioid receptors. In cAMP-based functional assays, compounds 7, 8b, and 10e behaved as KOR agonists, with compound 10e displaying the highest potency (EC50 = 1.41 nM). However, in Tango assays, compound 10e displayed a higher EC50 value of 4912 nM, suggesting G-protein biased signaling. In vivo,10e produced dose-dependent antinociceptive activity in the acetic-acid writhing assay and robust antipruritic effects, while showing no effect in the hot-plate test at doses up to 40 mg/kg. These findings demonstrate that incorporating a 7α-piperazinyl substituent into the 4,5-epoxymorphinan framework yields a highly potent and KOR-selective agonist, and highlight the critical role of the terminal phenylacetamido group in modulating receptor affinity and subtype selectivity.