Development of novel therapeutics for opioid dependence

开发阿片类药物依赖的新疗法

基本信息

批准号：
10475113
负责人：
Theodore M Kamenecka
金额：
$ 197.25万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475113
关键词：
Abstinence Adrenergic Agonists Agonist Animal Model Attenuated Behavior Biological Assay Brain Cells Cessation of life Chemicals Collaborations Cyclic AMP Data Death Rate Development Disease Drug Antagonism Drug Kinetics Economic Burden Electrophysiology (science)Ensure FDA approved G-Protein-Coupled Receptors Habenula Health Human In Vitro Individual Interdisciplinary Study Intravenous Knowledge Laboratories Ligands Luciferases Maintenance Medial Mediating Monitor Morphine Motivation Mus Nature Neurons Opiate Addiction Opioid Opioid Receptor Opioid agonist Orphan Overdose Oxycodone Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Phase Physiological Physiology Play Procedures Property Relapse Research Research Personnel Resistance Rewards Role Scientist Self Administration Series Serum Response Element Slice Societies Stimulant Structure-Activity Relationship Substance Use Disorder Substance Withdrawal Syndrome Therapeutic Time Toxic effect United States addiction antagonist arrestin 2 associated symptom base density drug development drug discovery drug metabolism high throughput screening illicit opioid in vivo lead optimization mu opioid receptors novel novel therapeutics null mutation opioid mortality opioid overdose opioid use opioid use disorder opioid withdrawal overdose death premature prevent programs receptor receptor function receptor internalization recruit reduce symptoms response small molecule statistics substance use treatment success therapeutic development tool trend

项目摘要

PROJECT SUMMARY This application is submitted in response to RFA-DA-19-002, Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3). The application describes a highly integrated project aimed at developing novel Gpr151 antagonists to facilitate long-term abstinence in opioid-dependent individuals. Gpr151 is an orphan G-protein coupled receptor (GPCR) that is expressed almost exclusively in the medial habenula. In exciting new data, we demonstrate that Gpr151 co-localizes with μ opioid receptors in the medial habenula and that this orphan receptor regulates the inhibitory effects of opioids on habenular neurons. Moreover, we show that Gpr151 plays a critical role in regulating the motivational properties of opioid drugs such as morphine and oxycodone in mice. Specifically, we find mice with null mutation in Gpr151 (Gpr151-/- mice) are resistant to the stimulant and rewarding effects of these opioids and self-administer lower quantities of oxycodone. Here, we propose to leverage this new knowledge, in conjunction with our expertise in small molecule drug development, to identify and optimize novel Gpr151 antagonists for the treatment of opioid dependence in humans. As Gpr151 is an orphan receptor for which there are no known ligands, the lack of potent agonists can hamper the identification of novel antagonists. However, we have now developed robust cell-based assays (and appropriate counter-screens) to reliably monitor Gpr151 function and used these assays to identify novel Gpr151 agonists. During the UG3 phase of this application, we will optimize this series of agonists to increase their potency and selectivity for Gpr151 (12 months). Once optimized, we will use potent and selective agonists from this series to facilitate the identification of novel antagonists at Gpr151 derived from the same or related chemical series (primary strategy) or via high-throughput screening (backup strategy) (12 months). Identification of novel Gpr151 antagonists will trigger the transition to the UH3 phase of the project. During the UH3 phase, we will employ an iterative medicinal chemistry based on structure-activity relationships (SAR) to optimize the potency and selectivity of novel Gpr151 receptor antagonists. SAR will also be used to optimize these antagonists for drug metabolism and pharmacokinetics (DMPK) and brain penetration properties, and identify those that are least likely to have toxicity in humans. We will assess the effects of those with the most favorable drug-like physiochemical properties on electrophysiological responses of medial habenula to opioid drugs. In addition, we will assess the in vivo efficacy these novel antagonists using the intravenous oxycodone self-administration and reinstatement of extinguished responding procedures in wild-type and Gpr151-/- mice. This multidisciplinary research plan will capitalize on the unique relevant scientific and drug discovery expertise of our team of committed investigators to develop novel therapeutics to facilitate abstinence in opioid-dependent individuals.

项目摘要该申请是针对RFA-DA-19-002的响应提交的，开发了预防和治疗的药物阿片类药物使用障碍和过量服用（UG3/UH3）。该应用程序描述了一个高度集成的项目开发新型的GPR151拮抗剂，以促进阿片类药物依赖性个体的长期戒烟。 GPR151 是一种孤儿G蛋白偶联受体（GPCR），几乎完全在媒体中表达。在令人兴奋的新数据，我们证明了GPR151与内侧Habenula和该孤儿受体调节卵巢神经元的抑制作用。而且，我们显示 GPR151在调查阿片类药物（例如吗啡和吗啡）的动机特性中起着至关重要的作用小鼠中的羟考酮。具体而言，我们发现在GPR151（GPR151 - / - 小鼠）中具有无效突变的小鼠具有抗性这些阿片类药物的刺激性和奖励作用和自我辅助量较低的羟考酮。在这里，我们提议利用这一新知识，以及我们在小分子药物开发方面的专业知识，识别和优化新型的GPR151拮抗剂来治疗人类的阿片类药物依赖性。作为GPR151 是一个没有已知配体的孤儿受体，缺乏潜在激动剂会阻碍鉴定新型拮抗剂。但是，我们现在开发了强大的基于细胞的测定法（适当相反的屏幕）可靠监控GPR151功能，并使用这些测定方法识别新型的GPR151激动剂。在本应用程序的UG3阶段，我们将优化这一系列激动剂，以提高其效力和 GPR151的选择性（12个月）。一旦优化，我们将使用该系列中的潜在和选择性激动剂到促进从同一或相关化学系列的GPR151处的新型拮抗剂的鉴定（主要策略）或通过高通量筛选（备份策略）（12个月）。新型GPR151的识别对手会触发向项目的UH3阶段的过渡。在UH3阶段，我们将采用基于结构活性关系（SAR）的迭代医学化学反应，以优化效力和新型GPR151受体拮抗剂的选择性。 SAR还将用于优化这些药物的拮抗剂代谢和药代动力学（DMPK）和大脑渗透特性，并确定那些最小的可能对人类有毒性。我们将评估类似药物最有利的人的影响内侧Habenula对阿片类药物的电生理反应的理化特性。另外，我们将使用静脉内羟考酮自我给药评估这些新型拮抗剂的体内效率和恢复野生型和GPR151 - / - 小鼠中熄灭的响应程序。这个多学科研究计划将利用我们团队的独特相关科学和药物发现专家承诺研究人员开发新的疗法，以促进阿片类药物依赖性个体的戒酒。