# Fragment-based Discovery of COMT Inhibitors as a Novel Pharmacotherapy for Alcoholism

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $215,824

## Abstract

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.

## Key facts

- **NIH application ID:** 10667129
- **Project number:** 1R21AA030630-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SETH M COHEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $215,824
- **Award type:** 1
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10667129

## Citation

> US National Institutes of Health, RePORTER application 10667129, Fragment-based Discovery of COMT Inhibitors as a Novel Pharmacotherapy for Alcoholism (1R21AA030630-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10667129. Licensed CC0.

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