Kappa Opioid Receptor Antagonists as Potential Therapeutics for Mood and Substance Use Disorders

The kappa opioid receptor (KOR) and its primary cognate ligands, the dynorphin peptides, are involved in diverse physiological processes. Disruptions to the KOR/dynorphin system have been found to likely play a role in multiple neuropsychological disorders, and hence KOR has emerged as a potential therapeutic target. Targeting KOR is complicated by close homology to the mu and delta opioid receptors (MOR and DOR), and many KOR ligands have at least moderate affinity to MOR and/or DOR. Animal models utilizing primarily very long-lasting selective KOR antagonists (>3 weeks following a single dose) have demonstrated that KOR antagonism attenuates certain anxiety-like and depression-like behaviors and blocks stress- and cue-induced reinstatement to drug seeking. Recently, relatively selective KOR antagonists with medication-like pharmacokinetic and pharmacodynamic properties and durations of action have been developed. One of these, JNJ-67953964 (also referred to as CERC-501, LY2456302, OpraKappa or Aticaprant) has been studied in humans, and shown to be safe, relatively KOR selective, and able to substantially attenuate binding of a KOR PET tracer to CNS localized KOR for greater than 24 h. While animal studies have indicated that compounds of this structural class are capable of normalizing withdrawal signs in animal models of cocaine and alcohol dependence and reducing cocaine and alcohol intake/seeking, additional studies are needed to determine the value of these second generation KOR antagonists in treating mood disorders and substance use disorders in humans.