PROJECT SUMMARY Catechol O-methyltransferase (COMT) is a Mg2+-dependent metalloenzyme responsible for O-methylation of endogenous neurotransmitters, hormones, and xenobiotic substances that possess a catechol functional group. Catecholamines are common neurotransmitters and inhibition of COMT has emerged as a strategy for treating central and peripheral nervous system disorders, such as Parkinson’s Disease, depression, cognition improvement, and others. Similarly, alcohol use disorder (AUD) is characterized by impaired cognitive control, that is due, in part, to dopamine regulation and signaling in the prefrontal cortex. Therefore, strategies that refine dopamine activity in the brain could be used to reduce alcohol dependence and improve cognition and decision-making associated with alcoholism. Indeed, tolcapone, a clinically approved COMT inhibitor, has been successfully shown to significantly reduced alcohol consumption. Despite these encouraging findings, tolcapone has many drawbacks, including hepatoxicity, which limits its widespread use. This proposal will use metalloenzyme fragment- based drug discovery (mFBDD) for developing COMT inhibitors that target the immutable active site Mg2+ ion. Our program will overcome the dependence of all clinical COMT inhibitors (including tolcapone) on the 3-nitrocatechol warhead. This effort will identify non-3-nitrocatechol warheads for COMT inhibitors that will be evaluated in an animal model of AUD. Collectively, this program will discovery best-in-class COMT inhibitors and demonstrate their utility as a novel therapeutic approach against AUD.

PROJECT NARRATIVE Alcoholism remains a leading cause of death and disability, in need of new therapeutic interventions. The proposed research will focus on innovative approaches to inhibiting the enzyme catechol O-methyltransferase (COMT), which has been linked to alcohol use disorder (AUD), and could provide a new pathway for addressing this devastating disease.