Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders

Abstract

Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.

A randomized, double‐blind, placebo‐controlled study of the kappa opioid receptor antagonist, CERC‐501, in a human laboratory model of smoking behavior

“…Preclinical data indicate that selective KOR antagonists produce anxiolytic and antidepressant effects in rodent models . Additionally, KOR antagonists have been shown to decrease the self‐administration of and withdrawal symptoms from nicotine, alcohol, and cocaine . CERC‐501 (previously known as LY2456302) is an orally bioavailable, high‐affinity, selective KOR antagonist .…”

Kappa-opioid antagonists as stress resilience medications for the treatment of alcohol use disorders

“…Whether long-acting kappa antagonists produce cardiovascular toxicity as a class effect is not known, and additional studies are required to determine whether conventional or inactivating kappa receptor antagonists are safer and more effective. Nevertheless, drug development is currently focused on the conventional antagonists because of the perception that these would be more 'drug-like', and the preclinical study of CERC-501 by Domi et al [5], published in this issue of Neuropsychopharmacology is an important advance in this translational effort.…”

Strengthening peptide-based drug activity with novel glyconanoparticle

“…In the case of Dynantin, the degree to which stability in plasma was improved was parallel to the degree of peptide entrapment. In the development of KOR antagonists there is a defined link between stability, activity, and overall efficacy that must be obtained [ 46 ]. An antagonist that is too stable will produce long-lasting effects that are likely to have negative consequences, while an antagonist that lacks an appropriate level of stability will be degraded too quickly to be effective.…”

“…The first peptide is dynantin ( Fig 1 ), which is a dynorphin A analogue with potent selectivity and antagonistic activity at the kappa opioid receptor (KOR) developed in Schiller’s research group [ 43 ]. KOR antagonists show promise as potential treatments for addiction and its associated depression that do not cause dependence, or show the high relapse rates associated with current treatment options [ 44 – 46 ]. The prototypical KOR antagonist nor-binaltorphimine (nor-BNI) is very stable in the body, however, its long lasting effects limit its clinical use [ 47 – 49 ].…”

“…The prototypical KOR antagonist nor-binaltorphimine (nor-BNI) is very stable in the body, however, its long lasting effects limit its clinical use [ 47 – 49 ]. Peptide structures that are capable of binding to the KOR, including dynorphin A analogues, are known to be less stable in the body and provide effects that are more transient [ 46 ]. Dynantin has the same chemical structure as dynorphin A (1–11)-NH 2 but with a (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp] group replacing the Tyr 1 residue [ 43 ], and contains many of the same proteolytic cleavage sites as dynorphin A, which itself is not stable in plasma [ 17 , 50 ].…”