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

项目总结 儿茶酚O-甲基转移酶(COMT)是一种依赖于镁的金属酶，负责 内源性神经递质、激素和外来物质的O-甲基化 具有邻苯二酚官能团。儿茶酚胺是常见的神经递质和 抑制COMT已成为治疗中枢和外周神经系统的一种策略 障碍，如帕金森氏症、抑郁症、认知改善等。 同样，酒精使用障碍(AUD)的特征是认知控制受损，这是由于， 在一定程度上，与前额叶皮质中的多巴胺调节和信号传递有关。因此，那些 改善大脑中的多巴胺活性可以用来减少酒精依赖和改善 与酒精中毒有关的认知和决策。事实上，托卡彭，一种临床上的 批准的COMT抑制剂，已被成功证明可显著减少酒精含量 消费。尽管有这些令人鼓舞的发现，Tolcapone仍有许多缺点，包括 肝毒性，这限制了它的广泛使用。这项提议将使用金属酶片段- 基于药物发现(MFBDD)开发针对不变活性的COMT抑制剂 站点管理2离子。我们的计划将克服所有临床COMT抑制剂(包括 Tolcapone)在3-硝基邻苯二酚弹头上。这一努力将识别非3-硝基邻苯二酚弹头 对于COMT抑制剂，将在AUD的动物模型中进行评估。总而言之，这个项目 将发现同类最佳的COMT抑制剂并展示其作为一种新的治疗方法的效用 针对澳元的做法。

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.