A potent, selective kappa opioid receptor (KOR) antagonist was being developed as an adjunctive treatment of major depressive disorder (MDD) and for substance use disorders.
In August 2017, we divested CERC-501 to Janssen Pharmaceuticals, a J&J Company, who are presently conducting a Phase II study.1
Kappa opioid receptors (KORs) and their native ligand dynorphin are localized in areas of the brain that affect reward and stress and may play a key role in mood, stress, and addictive disorders.1,2
Chronic stress leads to increased dynorphin expression, activating KORs and subsequent downstream signaling pathways to inhibit mesolimbic dopamine surge, contributing to negative affective states.3,4
KOR antagonists induce antidepressant-like effects in animal models and attenuate the anxiety behaviors associated with withdrawal. Accordingly, the therapeutic potential of KOR antagonism has been demonstrated in animal models of anhedonia, depression, and anxiety.5,6
Mechanistic validation: Phase 2 data for ALKS-5461, believed to be a “functional” KOR antagonist, in treatment-resistant depression
1. Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 2010;1314:44-55.
2. Knoll AT, Carlezon WA, Jr. Dynorphin, stress, and depression. Brain Res. 2010;1314:56-73.
3. Carr GV, Bangasser DA, Bethea T, Young M, Valentino RJ, Lucki I. Antidepressant-like effects of kappa-opioid
receptor antagonists in Wistar Kyoto rats. Neuropsychopharmacology. 2010;35(3):752-763.
4. Van't Veer A, Carlezon WA, Jr. Role of kappa-opioid receptors in stress and anxiety-related behavior.
Psychopharmacology (Berl). 2013;229(3):435-452.
5. Mague SD, Pliakas AM, Todtenkopf MS, et al. Antidepressant-like effects of kappa-opioid receptor antagonists in
the forced swim test in rats. J Pharmacol Exp Ther. 2003;305(1):323-330.
6. Rorick-Kehn LM, Witkin JM, Statnick MA, 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.