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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SUMMMARY