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

发现下一代 ALDH2 抑制剂，以减少酒精使用障碍患者的渴望和饮酒量

基本信息

批准号：
10324393
负责人：
Brent Blackburn
金额：
$ 22.45万
依托单位：
AMYGDALA NEUROSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-10 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324393
关键词：
Addictive Behavior Adult Affect Alcohol consumption Alcohol withdrawal syndrome Alcohols Alleles American Amygdaloid structure Anxiety Binding Bioavailable Biological Assay Brain Carbohydrates Cell Line Cell physiology Chemicals Clinical Clinical Data Cocaine Complex Computer Assisted Computer-Aided Design Conditioned Reflex Cues Development Disease Disulfiram Dopamine Drug usage Economics Enzymes Fatty Acids Female Genes Goals Grant Hepatocyte Hepatotoxicity Heroin Human In Vitro Individual Investigational New Drug Application Knock-out Knowledge Lead Longevity Mediating Medical Metabolism Methamphetamine Modeling Mus Neurosciences Nicotine Nucleus Accumbens Oral Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Phase Preclinical Testing Process Property Proteins Psychological reinforcement Publishing Research Support Rewards Self Administration Sensitivity and Specificity Small Business Innovation Research Grant Societies Structure-Activity Relationship Substance Use Disorder Technology United States Work addiction alcohol abuse therapy alcohol craving alcohol prevention alcohol risk alcohol use disorder aldehyde dehydrogenase 1 aldehyde dehydrogenases binge drinking cell immortalization clinical development craving drug seeking behavior economic cost experience in vitro Assay in vivo inhibitor/antagonist innovation invention liver injury next generation novel pharmacophore pre-clinical psychologic remifentanil screening social success suicide inhibitor

项目摘要

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

项目概要酒精使用障碍 (AUD) 影响着全世界 7600 万成年人，其中包括 1800 万美国人，并且对严重的医疗、心理、社会、经济和个人问题负有责任 (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330亿美元每年用于治疗药物滥用障碍 (SUD) 的费用不到 4% 药物治疗 (3).双硫仑，一种非竞争性、不可逆（自杀性）ALDH2 和 ALDH1 抑制剂 (4) (5) 用于治疗 AUD 已有 50 多年的历史 (6)。不幸的是，双硫仑是一种更有效的抑制剂 ALDH1 还抑制 ALDH5，并且似乎非选择性地与许多其他酶和蛋白质结合，导致不良的脱靶效应（7）。对于更好的治疗和更大的利用，显然存在未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) 的激增会驱动渴望和通过奖励回路的成瘾行为（9）。引发对酒精渴望的条件反应寻求药物的行为常常导致大量使用。事实上，在吸毒后，强烈的渴望仍会持续很长时间。停止（8）。酒精和其他成瘾物质会刺激伏隔核中 DA 水平的增加，它似乎介导大脑中的奖励或强化过程 (10) (11) (12)。选择性、可逆性抑制乙醛脱氢酶 2 (ALDH2) 已被证明可以 i) 减少自身服用酒精、尼古丁、可卡因和瑞芬太尼 (13) (14) (15)； ii) 减少提示恢复酒精、可卡因、甲基苯丙胺 (13) (14) 和海洛因 (16)； iii) 减少对碳水化合物的异常渴望和脂肪酸(17)； iv) 预防酒精戒断焦虑以及其他引起焦虑的原因 (18)。最近，敲除小鼠体内 ALDH2 活性可减少饮酒总量和酗酒 (19)。此外，杂合子或纯合子或 ALDH2*2 等位基因的个体活性显着降低或缺失与野生型 ALDH2 基因携带者相比，ALDH2 的存在和 AUD 的风险较低，且不影响寿命 (20) (21)。显然，减少 ALDH2 活性可降低 AUD 风险。此外，我们发表的临床前研究结果表明治疗其他成瘾性疾病的附加价值。我们的目标是实施创新的筛选技术来发明新的化合物有效、选择性和可逆的 ALDH2 抑制剂，用于安全治疗 AUD 患者。药品优化是一项多目标任务，是一个集成结构知识的迭代过程所需特性（ALDH2 抑制）和不需要特性的活性关系。这一过程将得到以下方面的帮助计算机辅助设计和药效团建模 (33)。 1