Exploring the Applicability of Potential Negative Allosteric Modulators at the Mu Opioid Receptor

探索 Mu 阿片受体潜在负变构调节剂的适用性

基本信息

批准号：
10607645
负责人：
Taryn Bosquez-Berger
金额：
$ 3.18万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
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：
2023-01-05 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10607645
关键词：
Acute Adenylate Cyclase Affinity Agonist Allosteric Site Analgesics Antidotes Asphyxia Binding Binding Sites Biological Assay Brain Buprenorphine CNR1 gene Cannabidiol Cannabinoids Cells Cessation of life Chronic Climate Core Facility Cyclic AMP Cyclic AMP-Dependent Protein Kinases Dose Drug Addiction Economics Enzyme Inhibition Feeling Fentanyl G-Protein-Coupled Receptors Gills Goals Grooming Human Image Immersion In Vitro Indiana Individual Intake Journals Ligands Measures Membrane Proteins Mentorship Methadone Modeling Modern Medicine Mus Naloxone Naltrexone Nature Neurosciences Opiate Addiction Opioid Opioid Antagonist Opioid Receptor Overdose Pain Pathway interactions Persons Pharmaceutical Preparations Physical Dependence Police Prevalence Property Proteins Provider Receptor Signaling Reporting Research Support Resources Rewards Scientist Second Messenger Systems Series Severities Signal Pathway Signal Transduction Site Spices Tail Techniques Testing Time Training Translating United States Universities Up-Regulation Variant Ventilatory Depression Visit Water Withdrawal Withdrawal Symptom Wooden Chest Syndrome Work abuse liability addiction analog antagonist antinociception anxiety-like behavior bath salts biological research carfentanil cathinone drug of abuse dysphoria emergency settings experience extracellular fentanyl analog in vivo in vivo Model in vivo evaluation mortality mouse model mu opioid receptors negative affect neuroadaptation novel opioid epidemic opioid mortality opioid overdose opioid use pharmacologic prevent programs receptor responsible research conduct screening symposium synthetic opioid

项目摘要

Project Summary/Abstract We are experiencing the third wave of opiates, a shift to powerful synthetics that is mirrored in other drugs of abuse such as cannabinoids (Spice) and cathinones (‘bath salts’). These potent drugs are preferred by dealers for economic reasons, but many of the new synthetic opiates bind so tightly to their target receptor, that the current treatment (naloxone/Narcan) for opioid overdose can prove ineffective. There are police reports of victims of synthetic opiate overdose found with multiple expended doses of naloxone, or who need IV administration. In the case of fentanyl-associated ‘wooden chest syndrome’, even a trained CPR provider cannot prevent death by asphyxiation. Where a competitive antagonist struggles against carfentanyl, a negative allosteric modulator may succeed. These molecules act via secondary sites on the receptor. Two candidate compounds have been identified; we hypothesize that negative allosteric modulators at the mu opioid receptors (µORs) can serve as an alternative strategy to overcome potent synthetic opiates, with the goal of alleviating the fatality of opioid toxicity. The project involves an iterative series of tests of structural analogues of these candidate negative allosteric modulators for their ability to reverse opiate signaling both in vitro and in vivo. The goal is to develop an optimized negative allosteric modulator at the µOR that would reverse opiate overdose in an emergency setting. Due to the nature of allosteric modulators, there is reason to expect that this would also avoid the strong withdrawal symptoms elicited by naloxone in opiate-dependent individuals, which is also an advantage in an emergency setting. Such a compound may also have superior pharmacological properties to naltrexone in places where methadone/buprenorphine are unavailable. With the current climate of the opioid crisis, it is crucial to explore the implications of the negative allosteric modulators, as it could lead to an alternative antidote to the increasingly powerful opiates that are being seen. Indiana University is a large university with a strength in biological research and particularly in drugs of abuse such as cannabinoids and opiates; the university also features many scientific resources (e.g. core facilities) to support research. The neuroscience program is highly interactive thanks in part to the Gill Center that sponsors an annual Symposium, visiting speakers, and a journal club. A training plan has been developed that covers techniques (in vitro and in vivo assays), coursework, training in the responsible conduct of research, as well as mentorship in some of the less tangible, but nonetheless essential, qualities that make for a successful scientist.

项目摘要/摘要我们正在经历第三波鸦片，这是向强大合成剂的转变，在其他滥用药物中都反映了这样作为大麻素（香料）和Cathinones（“浴沙拉”）。出于经济原因，经销商首选这些有效的药物，但许多新的合成职业与目标受体紧密结合，以至于目前的治疗（纳洛酮/纳尔坎）用于阿片类药物过量可证明无效。警方有报道称违反合成手术过量的事件发现多个花费了纳洛酮的剂量，或者需要静脉注射。在芬太尼相关的“木制胸部综合症”的情况下，即使是训练有素的CPR提供者也无法通过窒息来防止死亡。竞争性的对手斗争的地方 Carfentanyl，负变构调节剂可能会成功。这些分子通过接收器上的次要位点起作用。二候选化合物已被鉴定出来；我们假设MU阿片受体的负变构调节剂（µORS）可以作为克服潜在合成职业的替代策略，目的是减轻死亡阿片类药物毒性。该项目涉及这些候选者负构构的结构类似物的一系列迭代测试调节剂的能力在体外和体内逆向优化信号。目标是开发优化的负面 µOR处的变构调节器将在紧急情况下逆转过量用药。由于变构的性质调节器，有理由期望这也可以避免纳洛酮在鸦片依赖的个体，这在紧急情况下也是一个优势。这样的化合物也可能具有优越性纳曲酮的药理学特性在无法获得的方法adone/丁丙诺啡的地方。与电流阿片类药物危机的气候，探索负变构调节剂的含义至关重要，因为它可能导致对正在看到的日益强大的操作的替代解毒剂。印第安纳大学是一所大大学，在生物学研究方面具有力量大麻素和优化；该大学还拥有许多科学资源（例如核心设施）来支持研究。神经科学计划高度互动，部分原因是吉尔中心（Gill Center）赞助了年度研讨会，访问演讲者和期刊俱乐部。已经制定了涵盖技术（体外和体内测定）的培训计划，课程工作，负责任进行研究的培训以及一些不太明显的训练，但尽管如此，基本的特质是成功的科学家。