Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence.

The κ-opioid receptor (KOP-r) system and its endogenous ligands, the dynorphins, are involved in the neurobiological regulation of addictive states, and of mood. There are limited data on the impact of selective KOP-r antagonism in humans on basic biobehavioral functions, or on addictive diseases and mood disorders. Previously studied selective KOP-r antagonists have unusual pharmacodynamic and pharmacokinetic properties (slow development of KOP-r selectivity, extremely long duration of action) that limit translation to human studies. A recently developed selective KOP-r-antagonist, Opra Kappa (LY2456302; CERC-501), has medication-like duration of action, oral bioavailability, and target engagement. The current study is the first investigation of the effects of a KOP-r-antagonist in cocaine-dependent persons in comparison with normal volunteers. In a stress-minimized inpatient setting, we determined the neuroendocrine and neurobehavioral effects of repeated administration of an active dose of Opra Kappa (10 mg p.o. daily, four consecutive days in comparison with an initial baseline day). Healthy volunteers (n=40), persons diagnosed with cocaine dependence in early abstinence (<2 months, EACD) (n=23), and drug-free former cocaine-dependent persons (7-month to 25-year abstinence, DFFCD) (n=7) were studied, with measurements including circulating neuroendocrine hormones, affect, and, in cocaine-dependent persons, cocaine craving. Modest adverse events related to Opra Kappa included pruritus, observed in a subset of individuals. No significant change was observed in serum prolactin levels following Opra Kappa administration, but modest increases in circulating adrenocorticotropic hormone and cortisol were observed. No significant changes were noted in measures of depression or cocaine craving in this stress-minimized setting. Overall, these studies demonstrate that effects of 10 mg Opra Kappa are largely consistent with those predicted for a selective KOP-r antagonist. This medication regimen was tolerable, and is therefore feasible for further studies in cocaine-dependent persons.