Anticoagulation with no bleeding complications is the current objective of drug discovery programs in the area of treating and/or preventing thromboembolism. Despite the promises of therapeutics ta...

Opioid use disorder (OUD) has been recognized for many years as a leading public health emergency in the United States, costing almost 80,000 Americans their lives in 2023. Recently, fentanyl, the predominant synthetic opioid implicated in OUD, has begun to be adulterated with the alpha-2 adrenergic receptor (α₂AR) agonists xylazine and medetomidine. This has a profound effect on the treatment of suspected overdoses, as naloxone, which reverses fentanyl overdoses, does not reverse α₂ agonist overdoses, and there are no FDA-approved treatments for overdoses with an α₂ agonist. Xylazine is spreading rapidly through the illicit drug supply in the United States, and to further complicate efforts to mitigate its effects, xylazine users frequently experience necrotic wounds which are difficult to treat. In this review, we comprehensively examined literature sources to compile information on the pharmacology, chemistry, pharmacokinetics, and toxicities of α₂AR agonists that are implicated in OUD. We hope that this summary will provide a perspective on the way forward in combating the issue of α₂ agonist-adulterated opioids and lead to the discovery of drugs as reversal agents for α₂ agonist overdoses.

IntroductionOpioids have served as a cornerstone in pain management for decades. However, the emergence of increasingly potent synthetic analogs brings forth a range of side effects, including respiratory depression, tolerance, dependence, constipation, and, more importantly, the development of severe and debilitating opioid use disorder (OUD). Search for therapeutics to mitigate OUD has been challenging, and this has called for novel approaches that include the design of small molecules targeting neuronal circuits involved in addiction (opioid, dopamine, serotonin, norepinephrine, and glutamate receptors, etc.).Areas coveredIn this review, we retrieve and discuss two dozen (24) relevant patents filed in the past six (6) years that focus on novel small-molecule therapeutics for OUD. The chemical entities disclosed were highlighted, and specific examples were provided where necessary.Expert opinionSeveral chemical entities targeting both opioid and non-opioid targets are under consideration for treating OUD. Our search for patents covering such compounds revealed embodiments with diverse chemistry. Understanding the public impact of OUD and the rapidly evolving landscape of substance abuse underscores the urgent need for a thorough reevaluation of strategies to address these challenges. This includes the development of small molecules with unique mechanisms of action for OUD treatment.