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

项目摘要 儿茶酚O-甲基转移酶（COMT）是一种Mg 2+依赖性金属酶， 内源性神经递质、激素和异生物质的O-甲基化， 具有儿茶酚官能团。儿茶酚胺是常见的神经递质， COMT抑制已经成为治疗中枢和外周神经系统的策略 帕金森病、抑郁症、认知改善等。 类似地，酒精使用障碍（AUD）的特征是认知控制受损，这是由于， 在某种程度上，与前额叶皮层的多巴胺调节和信号传导有关。因此， 改善大脑中多巴胺的活性可以用来减少酒精依赖， 认知和决策与酗酒有关。事实上，托卡朋，临床上 已被批准的COMT抑制剂，已成功地显示出显着减少酒精 消费尽管这些令人鼓舞的发现，托卡朋有许多缺点，包括 肝毒性，这限制了其广泛使用。本方案将金属酶片段- 基于药物发现（mFBDD），用于开发靶向不可变活性的COMT抑制剂 Mg 2+离子。我们的计划将克服所有临床COMT抑制剂的依赖性（包括 tolcapone）在3-硝基儿茶酚弹头上。这项工作将确定非3-硝基儿茶酚弹头 对于COMT抑制剂，将在AUD动物模型中进行评估。总的来说，这个项目 将发现最好的COMT抑制剂，并证明其作为一种新型治疗药物的实用性 接近AUD。

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.