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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在过去的十年中，因药物过量导致的死亡人数急剧增加。药物干预已被证明对物质使用障碍具有变革性和挽救生命的作用，特别是阿片类药物成瘾和过量。如今，人们越来越有兴趣拥有一个供临床医生使用的医疗设备来解决药物使用障碍。共有三种治疗类别备受追捧的药物：替代品、减毒剂和解毒剂。有替代疗法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。对于替代方案，我们寻找能够在亚麻醉浓度下维持镇痛效果的麻醉剂。对于衰减器，我们寻求行为改变药物，如氯胺酮和地佐西平，已被证明可以减少自我给药动物模型中滥用药物，如可卡因、酒精、甲基苯丙胺、吗啡和尼古丁。作为决赛作为防线，我们努力发现新的药物过量解毒剂，以逆转滥用药物的毒性药物。在这些治疗类别中新化学物质的发现可能会导致开发治疗成瘾的新药物疗法，但对成瘾进行药理学修改哺乳动物模型中的行为评估成本高昂且具有挑战性。该提案的目的是加速新型小分子的发现和表征使用高通量筛选活体动物中的化合物来影响行为的分子行为分析，而不是生化或基于细胞的分析。我们的工作利用自动化数百只斑马鱼幼虫在神经活性物质影响下的行为的技术平台可以同时评估和比较化合物。它可以实现高通量筛选数千种化合物，用于那些感兴趣的表型神经活性药物。我们的中心前提方法是通过这些治疗类别进行药理学调节，它们独特的行为变化斑马鱼幼体的研究和新相关药理学的鉴定是相互关联的。据此，我们预测表型麻醉剂、氯胺酮或 PQ 的分子能够逆转苯二氮卓类药物镇静剂将成为滥用药物的替代品、减毒剂和解毒剂的新化学物质。从这里从角度来看，我们可以使用斑马鱼幼虫的高通量行为分析作为主要筛选结构多样的超过 100,000 种化合物。重要的是，从最初的试点屏幕开始，我们已经有了新的手中所有这些类别的化学物质。我们将使用最先进的成像技术进行机械研究斑马鱼中枢神经系统的研究有助于进一步表征新的药理学。的一个重要组成部分工作是将新发现的神经活性物质转化为啮齿动物的疼痛和物质使用模型失调。