New Technologies for Accelerating the Discovery and Characterization of Neuroactives that Address Substance Use Disorders

加速发现和表征解决药物使用障碍的神经活性物质的新技术

• 批准号: 10680754
• 负责人: Matthew N McCarroll
• 金额: $ 48.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680754
• 关键词: Acceleration; Acute; Addictive Behavior; Address; Affect; Alcohols; Analgesics; Anesthetics; Animal Model; Animals; Antidotes; Behavior; Behavioral; Behavioral Assay; Benzodiazepines; Biochemical; Biological Assay; Brain imaging; Cells; Central Nervous System; Cessation of life; Chemicals; Chemistry; Cocaine; Coupled; Development; Hand; Image; Intervention; Ketamine; Larva; Lead; Life; Methamphetamine; Modeling; Modification; Morphine; Neuroanatomy; Neuropharmacology; Nicotine; Opiate Addiction; Opioid; Overdose; Pain management; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenocopy; Primates; Rodent; Rodent Model; Sedation procedure; Self Administration; Substance Use Disorder; Technology; Therapeutic; Toxic effect; Translations; Work; Zebrafish; addiction; cost; dizocilpine; drug induced behavior; drug of abuse; experimental study; high throughput screening; in vivo; interest; new technology; novel; novel therapeutics; opioid overdose; pain model; pharmacologic; small molecule; technology platform

ABSTRACT Over the last decade, there has been a dramatic increase in deaths resulting from drug overdoses. Pharmacological interventions have proven to be transformative and life-saving in substance use disorders, particularly in opioid addictions and overdoses. Today, there is an increasing interest in having an armamentarium at clinician's disposal to address substance use disorders. There are three therapeutic classes of drugs that are highly sought: alternatives, attenuators, and antidotes. Having alternative therapeutic avenues for pain management other than opioids could help lower new addiction cases. For alternatives, we look to anesthetics that maintain analgesic effects at sub-anesthetic concentrations. For attenuators, we seek behavior-modifying drugs like ketamine and dizocilpine that have demonstrated reduced self-administration of drugs of abuse like cocaine, alcohol, methamphetamine, morphine, and nicotine in animal models. As a final line of defense, we endeavor to discover new drug overdose antidotes that reverse the toxicity of abused drugs. The discovery of novel chemical matter in these therapeutic classes could lead towards the development of new pharmacotherapies for treating addictions, but pharmacological modification of addictive behaviors in mammalian models is costly and challenging to evaluate. The objective of this proposal is to accelerate the discovery and characterization of novel small molecules affecting behavior using high-throughput screening of compounds in live animals guided by behavioral profiling as opposed to biochemical or cell-based assays. Our work exploits an automated technological platform in which the behaviors of hundreds of larval zebrafish under the influence of neuroactive compounds can be assessed and compared simultaneously. It enables the high-throughput screening of thousands of compounds for those that phenocopy neuroactive drugs of interest. The central premise of our approach is that pharmacological modulation by these therapeutic classes, their unique behavioral changes in larval zebrafish, and the identification of new related pharmacology are inter-connected. Accordingly, we predict that molecules that phenocopy anesthetics, ketamine, or the PQs ability to reverse benzodiazepine sedation will be new chemical matter for alternatives, attenuators, and antidotes of abused drugs. From this perspective, we can use the high-throughput behavioral assays in larval zebrafish as a primary screen of a structurally diverse set of >100,000 compounds. Importantly, from initial pilot screens we already have new chemical matter of all these classes in hand. We will perform mechanistic studies using state-of-the-art imaging of the zebrafish central nervous system to help further characterize new pharmacology. An essential part of the work is the translation of newly discovered neuroactives into rodent models of pain and substance use disorders.

摘要 在过去十年中，药物过量造成的死亡人数急剧增加。 药物干预已被证明是物质使用障碍的变革和挽救生命， 特别是阿片类药物成瘾和过量。今天，人们越来越感兴趣的是， 为临床医生提供医疗设备，以解决物质使用障碍问题。有三个治疗类 这些药物是非常受欢迎的：替代品，衰减剂和解毒剂。接受替代治疗 阿片类药物以外的疼痛管理途径可能有助于减少新的成瘾病例。对于替代品，我们 寻找在亚麻醉浓度下保持镇痛效果的麻醉剂。对于衰减器，我们寻求 行为改变药物，如氯胺酮和地佐环平，已证明减少自我管理， 滥用药物如可卡因、酒精、甲基苯丙胺、吗啡和尼古丁的动物模型。作为最终 防线，我们奋进发现新的药物过量解毒剂，扭转滥用的毒性 毒品在这些治疗类别中发现新的化学物质可能会导致 开发新的药物治疗成瘾，但成瘾药物的药理学修饰 在哺乳动物模型中的行为是昂贵的和具有挑战性的评估。 这项建议的目的是加快发现和表征新的小 在活体动物中高通量筛选影响行为的分子， 行为分析，而不是生物化学或基于细胞的测定。我们的工作利用了一种自动化的 一个技术平台，在这个平台上，数百只斑马鱼幼虫在神经活性物质的影响下， 可以同时评估和比较化合物。它能够高通量筛选 成千上万的化合物，用于那些表型复制感兴趣的神经活性药物。我们的核心前提是 方法是通过这些治疗类别的药理学调节，它们独特的行为变化， 斑马鱼幼体，并确定新的相关药理学是相互关联的。因此我们 预测分子的表型模仿麻醉剂，氯胺酮，或PQs的能力，以扭转苯二氮卓类 镇静剂将成为滥用药物的替代品、稀释剂和解毒剂的新化学物质。从这个 从这个角度来看，我们可以使用高通量的行为分析在幼虫斑马鱼作为一个初级筛选的一个 > 100，000种化合物的结构多样的集合。重要的是，从最初的试点屏幕，我们已经有了新的 所有这些种类的化学物质。我们将使用最先进的成像技术进行机制研究 斑马鱼中枢神经系统的研究，以帮助进一步表征新的药理学。的重要组成部分 工作是将新发现的神经活性物质转化为疼痛和物质使用的啮齿动物模型 紊乱