CERC-501

LY-2456302 is a potent and centrally-penetrant kappa opioid receptor antagonist with a Ki of 0.807 nM.

LY2456302 binds with high affinity to the human kappa opioid receptor with a 30-fold higher affinity over the human mu opioid receptor and 190-fold higher affinity over the human delta opioid receptor. LY2456302 shows no appreciable affinity for several non-opioid cell surface G-protein-coupled receptor targets, including monoaminergic, muscarinic, cholinergic, and adrenergic receptors or ion channel/transporter binding targets or the central benzodiazepine binding site[1].

LY2456302 has a rapid absorption (tmax=1-2 h) and good oral bioavailability (F=25%). Oral LY2456302 administration selectively and potently occupies central kappa opioid receptors (ED50=0.33 mg/kg), 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. LY2456302 produces antidepressant-like effects in the mouse forced swim test and enhances the effects of imipramine and citalopram. LY2456302 reduces ethanol self-administration in alcohol-preferring rats[1]. LY2456302 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withdrawal induced anxiety-related behavior, somatic signs, and CPA, and increased hotplate latency in nicotine withdrawn mice following pre-treatment[2].

References:
[1]. Rorick-Kehn LM, et al. LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. Neuropharmacology. 2014 Feb;77:131-44.
[2]. Jackson KJ, et al. Effects of orally-bioavailable short-acting kappa opioid receptor-selective antagonist LY2456302on nicotine withdrawal in mice. Neuropharmacology. 2015 Oct;97:270-4.