MKOP002, a novel bifunctional μ-/κ-opioid decapeptide with G protein-biased μ-opioid agonism, exhibits antinociceptive and antipruritic activities.

Opioid receptors, as members of the G-protein-coupled receptor (GPCR) superfamily, represent promising therapeutic targets for managing nociception. Herein, we designed, synthesized, and pharmacologically characterized the novel bifunctional decapeptide, MKOP002. In vitro, MKOP002 activated both µ- and κ-opioid receptors (MOR and KOR), exhibiting G protein-biased agonism at MOR. Subcutaneous (s.c.) injection of MKOP002 produced significant antinociceptive effects through the peripheral MOR and KOR in the tail-flick test. Notably, MKOP002 demonstrated potent and dose-dependent antinociceptive efficacy across various models of acute, inflammatory, and neuropathic pain. Additionally, MKOP002 exhibited antipruritic effects comparable to CR845, mediated by both the peripheral and central KOR. Similar to CR845, at the high doses, MKOP002 induced sedation via central KOR at least partially, and also resulted in depressive-like behaviors. Importantly, MKOP002 did not elicit MOR-associated adverse effects such as tolerance, constipation, respiratory depression, or addiction. These findings underscore the therapeutic potential of MKOP002 as a lead compound for antinociceptive and antipruritic therapy, supporting the development of bifunctional MOR/KOR agonists as a safer opioid strategy.