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

基于片段的 COMT 抑制剂的发现作为酒精中毒的新型药物疗法

基本信息

批准号：
10667129
负责人：
SETH M COHEN
金额：
$ 21.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667129
关键词：
Abstinence Active Sites Acute Address Alcohol consumption Alcohol dependence Alcoholism Animal Model Binding Biological Biophysics Brain Catechol O-Methyltransferase Catecholamines Catechols Cause of Death Central Nervous System Chronic Clinical Clinical Treatment Cognition Decision Making Dependence Development Disease Docking Dopamine Drug Kinetics Enzyme Inhibition Enzymes Ethanol FDA approved Family Goals Hepatotoxicity Hormones Hyperalgesia Impaired cognition Impulsivity Individual Intake Ions Lead Length Libraries Link Membrane Mental Depression Metals Methylation Modeling Neurotransmitters Parkinson Disease Pathway interactions Patients Peripheral Nervous System Diseases Prefrontal Cortex Procedures Property Rattus Regulation Relapse Research Safety Signal Transduction Societies Stress Therapeutic Withdrawal Xenobiotics alcohol use disorder alcoholism pharmacotherapy attenuation biophysical techniques cognitive control cost disability drug discovery experience functional group improved inhibitor innovation lead series loved ones metalloenzyme novel novel therapeutic intervention pharmacophore programs sex side effect small molecule inhibitor structural biology tolcapone trait

项目摘要

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.

项目概要儿茶酚 O-甲基转移酶 (COMT) 是一种 Mg2+ 依赖性金属酶，负责内源性神经递质、激素和外源物质的 O-甲基化儿茶酚胺是常见的神经递质，具有儿茶酚官能团。 COMT 抑制已成为治疗中枢和周围神经系统的策略疾病，如帕金森病、抑郁症、认知改善等。同样，酒精使用障碍（AUD）的特点是认知控制受损，这是由于，部分原因在于前额皮质中的多巴胺调节和信号传导。改善大脑中的多巴胺活动可用于减少酒精依赖并改善事实上，托卡彭是一种与酗酒有关的认知和决策。批准的 COMT 抑制剂，已成功证明可以显着减少酒精含量尽管有这些令人鼓舞的发现，托卡朋仍有许多缺点，包括肝毒性，限制了其广泛使用。该提案将使用金属酶片段。基于药物发现 (mFBDD)，用于开发针对不可变活性物质的 COMT 抑制剂我们的方案将克服所有临床 COMT 抑制剂（包括 tolcapone）在 3-硝基儿茶酚弹头上这项工作将识别非 3-硝基儿茶酚弹头。 COMT 抑制剂将在 AUD 动物模型中进行评估。将发现一流的 COMT 抑制剂并证明其作为治疗性小说的实用性兑澳元的做法。