Neurology; dermatology

Mouse and rat studies suggest a G protein-biased KOR agonist could help treat pain and itch without the sedation and dysphoria caused by unbiased KOR agonists. A previously reported triazole-based, biased KOR agonist activated KOR-dependent G-protein signaling and KOR-dependent ARRB2 recruitment with EC₅₀ values of 77.2 nM and 4.9 μM, respectively. In a mouse model of thermal pain, subcutaneous injection of the biased KOR agonist decreased thermal allodynia compared with subcutaneous vehicle. In a rat model of chemical-induced pain, the subcutaneous KOR agonist increased self-administered electrical brain stimulation - a behavior associated with the absence of either pain or dysphoria - compared with vehicle. In a mouse model of chemical-induced itch, the KOR agonist decreased scratching behavior. In mice, the biased KOR agonist did not cause sedation-related reductions in ambulatory activity, whereas the unbiased KOR agonist tool compound did. In rats, the biased KOR agonist increased self-administered electrical brain stimulation compared with the unbiased agonist. Next steps could include testing the biased KOR agonist in additional models of pain and itch.

Tioga Pharmaceuticals Inc. has asimadoline, a small molecule KOR agonist, in Phase III testing to treat irritable bowel syndrome and Phase II testing to treat itch and emesis...