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

摘要 在过去的十年里，药物过量导致的死亡人数急剧增加。 药物干预已被证明在物质使用障碍中具有变革性和救命性， 尤其是阿片类药物成瘾和过量。今天，人们对拥有一个 供临床医生使用的医疗设备，以解决物质使用障碍。有三个治疗班 备受追捧的药物：替代品、衰减剂和解毒剂。有替代疗法 阿片类药物以外的疼痛控制途径可能有助于降低新的成瘾病例。对于替代方案，我们 寻找在亚麻醉剂浓度下保持止痛效果的麻醉药。对于衰减器，我们寻求 行为改良药，如氯胺酮和地佐西平，显示出自我给药减少 在动物模型中滥用可卡因、酒精、甲基苯丙胺、吗啡和尼古丁等药物。作为期末考试 防线，我们努力发现新的药物过量解毒剂，逆转滥用的毒性 毒品。在这些治疗类中发现新的化学物质可能会导致 治疗成瘾的新药物疗法的发展，但成瘾药物的药理修饰 在哺乳动物模型中的行为评估是昂贵和具有挑战性的。 这项建议的目标是加速发现和表征新奇的小 通过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，与生化或基于细胞的分析相对。我们的工作利用了一种自动化的 数百条斑马鱼幼体在神经活动影响下的行为技术平台 化合物可以同时进行评估和比较。它使高通量筛选能够 数以千计的化合物适用于那些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物调节，他们独特的行为变化 斑马鱼幼体的鉴定与新的相关药理作用是相互联系的。因此，我们 预测表观麻醉剂、氯胺酮或PQS逆转苯二氮类药物的能力的分子 镇静将成为滥用药物的替代品、衰减剂和解毒剂的新化学物质。由此 前景来看，我们可以使用斑马鱼幼体的高通量行为分析作为初步筛选 结构多样的&gt；100,000化合物集。重要的是，从最初的试点屏幕来看，我们已经有了新的 所有这些课程的化学物质都在手中。我们将使用最先进的成像技术进行机械研究 对斑马鱼中枢神经系统的研究有助于进一步确定新的药理特性。这是一个重要的组成部分 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 精神错乱。

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.