Aticaprant (LY-2456302) (CERC-501) is a potent and centrally-penetrant antagonist of the kappa-opioid receptor (Ki: 0.807 nM).

Aticaprant binds with a high affinity to the human kappa opioid receptor with a 30-fold higher affinity over the human mu-opioid receptor and a 190-fold higher affinity over the human delta-opioid receptor. Aticaprant shows no appreciable affinity for several non-opioid cell surface G-protein-coupled receptor targets [1].

Aticaprant has rapid absorption (tmax=1-2 h) and good oral bioavailability (F=25%). Aticaprant selectively and potently occupies central kappa opioid receptors (ED50: 0.33 mg/kg, p.o.), without evidence of mu or delta receptor occupancy. LY2456302 potently blocks kappa-agonist-mediated analgesia and disruption of prepulse inhibition, without affecting mu-agonist-mediated effects at doses >30-fold higher. Aticaprant produces antidepressant-like effects in the mouse forced swim test and enhances the effects of imipramine and citalopram. Aticaprant reduces ethanol self-administration in alcohol-preferring rats [1]. Aticaprant alleviates the nicotine withdrawal syndrome, as evidenced by decreased expression of nicotine withdrawal-induced anxiety-related behavior, somatic signs, and CPA, and increased hotplate latency in nicotine withdrawn mice following pre-treatment [2].

Three male cannulated rats are administered a single 1 mg/kg intravenous (IV) and 10 mg/kg oral (PO) dose of Aticaprant to determine the pharmacokinetic parameters. Plasma samples are collected at 0.08 (IV only), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 h post-dose and analyzed by liquid chromatography coupled to tandem mass spectral detection to determine the concentrations of Aticaprant (CERC-501). Male mice are administered a single 10 mg/kg PO dose of Aticaprant to determine the pharmacokinetic parameters. Plasma samples are collected at 0.5, 1, 2, 4, 8, and 24 h post-dose and analyzed by LCMS/MS to determine the concentrations of Aticaprant. The plasma and brain binding of Aticaprant is determined by equilibrium dialysis at 1 μM [1].