ONO-2952

A novel potent, selective, orally active translocator protein 18 kDa (TSPO/PBR) antagonist with Ki of 0.33-9.3 nM for both rat and human TSPO; displays high selectivity over 98 other receptors, transporters, ion channels and enzymes; inhibits both neurosteroid accumulation and noradrenaline release in the brain of rats exposed to acute stress; suppresses conditioned fear stress-induced freezing behavior in rats with an efficacy equivalent to that of diazepam, but without not affect learning and memory. Irritable Bowel Syndrome Phase 2 Clinical

Signaling Pathways >> Others >> Others

Research Areas >> Neurological Disease

Ki: 0.33-9.30 nM (Rat and human TSPO)[1]

As for its selectivity for TSPO, ONO-2952 at a concentration of 10 μM showed good selectivity for TSPO against 98 off-targets (<50% inhibition). Determination of ONO-2952 Ki or IC50 values for the remaining 35 targets (50% inhibition at 10 μM) reveal Ki values of less than 1 μM only for 3 receptors, i.e. melatonin 2, progesterone B, and adrenergic α2C. The affinity of ONO-2952 for these receptors is at least 59 times lower than that for TSPO. ONO-2952 Ki value for the GABAA receptor is more than 600 times higher than that for TSPO[1].

ONO-2952 (0.03-3 mg/kg; oral administration; male Sprague Dawley rats) treatment dose-dependently suppresses restraint stress-induced defecation in rats with brain TSPO occupancy of more than 50%. ONO-2952 also suppresses conditioned fear stress-induced freezing behavior in rats[1]. ONO-2952 inhibits both neurosteroid accumulation and noradrenaline release in the brain of rats exposed to acute stress[1]. Animal Model: Male Sprague Dawley rats (8 weeks old) under conditioned fear stress test[1] Dosage: 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg Administration: Oral administration Result: Dose-dependently suppressed restraint stress-induced defecation in rats. And suppressed conditioned fear stress-induced freezing behavior in rats.

[1]. Mitsui K, et al. Anti-stress effects of ONO-2952, a novel translocator protein 18 kDa antagonist, in rats. Neuropharmacology. 2015 Dec;99:51-66.

[2]. Whitehead WE, et al. Randomised clinical trial: exploratory phase 2 study of ONO-2952 in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2017 Jan;45(1):14-26.