Investigational drugs for alcohol use disorders: a review of preclinical data

ABSTRACT

Introduction: Alcohol use disorders (AUDs) are one of the leading causes of preventable death in the developed world. In the U.S., only three FDA-approved pharmacotherapies for AUDs currently exist, but at a population level they display poor efficacy, low compliance rates, and adverse side effects. Therefore, identifying novel neurobiological targets for pharmacological treatment of AUDs is of urgent concern.

Areas covered: We discuss recent preclinical data on investigational drugs that have been assessed for their therapeutic potential in AUDs. We focus on three neurobiological domains underlying AUDs: neuropeptide systems, neuroinflammatory/neuroimmune mediators, and epigenetic modifications. We iterate the therapeutic potential of ghrelin receptor antagonists, oxytocin, neurokinin 1 receptor antagonists, and glucagon-like peptide-1 receptor agonists. In the context of neuroinflammatory/neuroimmune modulators, we draw attention to P2X4 receptor positive allosteric modulators and phosphodiesterase inhibitors. Finally, we highlight the prospects of histone deacetylase inhibitors and DNA methyltransferases that modulate the dysregulated epigenetic landscape in alcohol dependence.

Expert opinion: We propose that several of the compounds discussed may be suitable to be repurposed for AUD treatment. We allude to the possibility of combined pharmacotherapy for AUDs and anticipate the efforts that must be enacted to advance the field of personalised medicine for the treatment of this devastating condition.

KEYWORDS:

• Alcohol use disorders
• epigenetics
• neuroinflammation
• neuropeptides
• pharmacotherapies
• preclinical

Acknowledgment

We also acknowledge the Victorian Government State Infrastructure Program.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• There is a paucity of effective pharmacotherapies for alcohol use disorders.

• We discuss emerging preclinical evidence on investigational drugs targeting neuropeptide systems, neuroinflammatory/neuroimmune mediators, and epigenetic modifications as potential targets for AUD treatment.

• Neuropeptide targets include ghrelin receptor antagonists, oxytocin, neurokinin 1 receptor antagonists, and glucagon-like peptide-1 receptor agonists.

• Neuroinflammatory/neuroimmune mediators that show potential as pharmacotherapies for AUDs include P2X4 receptor positive allosteric modulators and phosphodiesterase inhibitors.

• Drugs targeting epigenetic mechanisms, such as inhibitors of histone deacetylase and DNA methyltransferase may also be therapeutically beneficial for AUDs.

• Many of the drugs discussed are already used clinically for other diseases and have the potential to be repurposed for the treatment of AUDs.

This box summarizes key points contained in the article.

Additional information

Funding

A. J. Lawrence is a Principal Fellow of the National Health & Medical Research Council Australia (1116930).