Discovery next generation inhibitors of ALDH2 to reduce craving and alcohol consumption in alcohol use disorders

SUMMARY项目 酒精使用障碍(AUD)影响着全球7600万成年人，其中包括1800万美国人，而且 对严重的医疗、心理、社会、经济和个人问题负责(1)。经济总量 在美国，澳元每年给社会造成的损失高达2240亿美元(2)。总计330亿美元是 每年用于治疗物质使用障碍(SUD)，不到4%的治疗费用用于 药物治疗(3)。ALDH2和ALDH1的非竞争性、不可逆(自杀)抑制剂双硫兰(4)(5) 已用于治疗澳门氏症超过50年(6)。不幸的是，双硫兰是一种更有效的抑制 ALDH1也抑制ALDH5，并且似乎非选择性地与许多其他酶和蛋白质结合，导致 产生不利的偏离目标的影响(7)。对更好的治疗和更大的利用率有明显的未得到满足的需求， 安全有效的药物疗法治疗AUD的机会很大。 AUD是一种复杂的疾病。Volkow和Koob(8)假设，多巴胺(DA)的激增会驱动欲望和 通过奖赏回路的成瘾行为(9)。引发饮酒欲望的条件性反应激发 寻求毒品的行为往往会导致大量使用。事实上，在吸毒后很长一段时间内，强烈的渴望会持续很长时间。 已停止(8)。酒精和其他成瘾剂刺激伏隔核多巴胺水平增加， 它似乎在大脑(10)(11)(12)中调节奖励或强化过程。 选择性、可逆地抑制乙醛脱氢酶2(ALDH2)已被证明：1)减少自身 给予酒精、尼古丁、可卡因和瑞芬太尼(13)(14)(15)；二)减少线索-恢复 酒精、可卡因、甲基苯丙胺(13)(14)和海洛因(16)；三)减少对碳水化合物的异常渴望 和脂肪酸(17)；以及(4)防止酒精戒断焦虑以及其他引起焦虑的原因(18)。最近， 小鼠体内ALDH2活性的敲除既减少了总饮酒量，也减少了酗酒(19)。此外， 杂合或纯合子或ALDH2*2等位基因的个体活动显著减少或缺失 与野生型ALDH2基因携带者相比，在不影响寿命的情况下，ALDH2基因携带者患AUD的风险较低(20) (21)。显然，ALDH2活性降低降低了AUD的风险。此外，我们发表的临床前研究结果 为其他成瘾障碍的治疗提供了额外的价值。 我们的目标是实施创新的筛选技术来发明新的化合物，这些化合物 有效的、选择性的和可逆的ALDH2抑制剂用于AUD患者的安全治疗。药效 优化是一项多目标的工作，是一个迭代的过程，它整合了结构知识-- 所需特性(ALDH2抑制)和非所需特性的活性关系。这一进程将得到以下帮助 计算机辅助设计和药效团建模(33)。 1

PROJECT SUMMMARY Alcohol use disorder (AUD) affects 76 million adults world-wide, including 18 million Americans, and is responsible for serious medical, psychological, social, economic, and personal problems (1). The total economic cost of AUD to society is a staggering $224 billion each year in the United States (2). A total of $33 billion is spent each year to treat substance use disorder (SUD), with less than 4% of treatment spending for pharmacotherapy (3). Disulfiram, a noncompetitive, irreversible (suicide) inhibitor of ALDH2 and ALDH1 (4) (5) has been used to treat AUD for more than 50 years (6). Unfortunately, disulfiram is a more potent inhibitor of ALDH1, also inhibits ALDH5, and appears to bind non-selectively to many other enzymes and proteins, leading to adverse off-target effects (7). There is a clear unmet need for better treatments and greater utilization, with a large opportunity for safe and effective pharmacotherapies to treat AUD. AUD is a complex disorder. Volkow and Koob (8) postulate that a surge of dopamine (DA) drives craving and addictive behavior through reward circuits (9). Conditioned responses that trigger craving for alcohol motivate drug-seeking behaviors often leading to heavy use. Indeed, strong cravings can persist long after drug use has stopped (8). Alcohol and other addictive agents stimulate an increase in DA levels in the nucleus accumbens, which appears to mediate reward or reinforcement processes in brain (10) (11) (12). Selective, reversible, inhibition of aldehyde dehydrogenase 2 (ALDH2) has been shown to i) reduce self- administration of alcohol, nicotine, cocaine, and remifentanil (13) (14) (15); ii) reduce cue-reinstatement of alcohol, cocaine, methamphetamine (13) (14), and heroin (16); iii) reduce abnormal cravings for carbohydrate and fatty acids (17); and iv) prevents alcohol withdrawal anxiety as well as other causes of anxiety (18). Recently, a knockout of ALDH2 activity in mice reduces both total drinking of alcohol and binge drinking (19). Furthermore, individuals who are hetero- or homozygous or for the ALDH2*2 allele have markedly reduced or absent activity of ALDH2 and a lower risk of AUD, without affecting longevity, compared to wild-type ALDH2 gene carriers (20) (21). Clearly, decreased ALDH2 activity lowers the risk of AUD. In addition, our published preclinical findings suggest additional value for treating other addiction disorders. Our objective is to implement an innovative screening technology to invent new compounds that are potent, selective, and reversible inhibitors of ALDH2 for the safe treatment of patients with AUD. Drug optimization is a multi-objective undertaking and is an iterative process that integrates knowledge of structure- activity relationships for desired (ALDH2 inhibition) and undesired properties. This process will be aided by computer aided design and pharmacophore modelling (33). 1