Extensive preclinical data support the proposal that kappa-opioid receptor antagonists may have therapeutic benefit for the treatment of mood disorders and drug addiction by promoting stress resilience [1]. People who are vulnerable to depression, anxiety, or addiction can become hypersensitive to stressful experience, which can act as a trigger for a recurrence of a mood disorder or substance use episode. The neuronal processes underlying these responses have been extensively studied in animal models where stress exposure can cause the release of stress neuropeptides including the endogenous dynorphin opioids in brain, which activate kappa-opioid receptors. Kappa receptor activation in animals and humans produces anxiety-like, dysphoric, aversive, and drug-seeking behavioral responses. Antagonists that block kappa-opioid receptors can reduce these stress responses and thereby have antidepressant and anti-addictive activity in animal models. For example, kappa antagonists block stress-potentiation of drug reward, block drug-seeking in substance-dependent animals, and block stress-induced reinstatement of drug self-administration. These beneficial effects of kappa antagonists are evident in behavioral assays using a wide range of addictive substances: cocaine, heroin, nicotine, ethanol, and methamphetamine [2]. In addition, kappa antagonists are effective in the preclinical behavioral assays predictive of antidepressant efficacy in humans [1]. Thus, kappa antagonists could theoretically have broad clinical utility, and the recognition of this opportunity has stimulated a new wave of drug development.

Clinical trials with buprenorphine (a nonselective drug having kappa receptor antagonist activity) support this concept [3], and several pharmaceutical companies have been actively developing selective kappa-opioid receptor antagonists for use in human studies. It is important to note that there are two different types of kappa antagonists: the initially introduced compounds (e.g., norbinalorphimine and JDTic) are highly selective KOR antagonists but can inactivate the kappa receptor for weeks (“receptor-inactivating antagonists”). The mechanism for long-lasting kappa receptor inactivation by this type of antagonist was recently described and involves the activation of a novel signaling pathway initiated by c-Jun Kinase [4]. The kappa receptor signaling complex undergoes as a structural change after antagonist binding that permanently inactivates signaling, even after drug dissociation. In contrast, short-acting kappa selective compounds have been synthesized that act as competitive inhibitors of agonist action (“conventional antagonists”). The short-acting kappa antagonist developed by Eli Lilly [(S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1yl)methyl)-phenoxy)benzamide], known as LY-2456302 or CERC-501, is the farthest along in clinical development, currently by Janssen Pharmaceuticals.

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