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

项目摘要/摘要 我们正在经历第三波鸦片类药物，转向强力合成药物，这在其他滥用药物中也有反映，如 如大麻素(香料)和卡西诺酮(浴盐)。出于经济原因，这些强效药物受到经销商的青睐，但 许多新的合成阿片类药物与它们的靶受体结合得如此紧密，以至于目前的治疗方法(纳洛酮/纳尔康) 阿片类药物过量可能被证明是无效的。有警方报告称，合成鸦片类药物过量的受害者被发现有多个 使用纳洛酮，或需要静脉注射的患者。在芬太尼相关的“木胸综合征”病例中， 即使是训练有素的心肺复苏提供者也不能防止窒息死亡。竞争对手与之抗争的地方 负性变构调节剂卡芬太尼可能会成功。这些分子通过受体上的第二位点起作用。二 已经确定了候选化合物；我们假设，u阿片受体上的负变构调节剂 (µORs)可以作为一种替代战略来克服有效的合成阿片剂，目标是减轻 阿片类药物中毒。该项目包括对这些候选负变构体的结构类似物进行一系列迭代测试 调节剂在体外和体内逆转阿片类信号的能力。我们的目标是开发一个优化的负片 µOR变构调节剂，可在紧急情况下逆转阿片类药物过量。由于变构的性质 调节剂，有理由预计这也将避免纳洛酮引起的强烈戒断症状 阿片依赖者，这在紧急情况下也是一种优势。这样一种化合物也可以具有更好的 在美沙酮/丁丙诺啡无法获得的地方，纳曲酮的药理学特性。随着潮流的发展 在阿片类药物危机的气候下，至关重要的是探索负变构调节剂的影响，因为它可能导致 一种替代日益强大的鸦片类药物的解毒剂。 印第安纳大学是一所大型大学，在生物研究方面，特别是在滥用药物方面，如 大麻素和鸦片类药物；该大学还拥有许多支持研究的科学资源(如核心设施)。 神经科学项目的互动性很强，这在一定程度上要归功于吉尔中心，该中心赞助了一年一度的研讨会，访问 演讲者，还有一个杂志俱乐部。已经制定了一项培训计划，涵盖各种技术(体外和体内测试)， 课程、负责任的研究行为方面的培训，以及一些不太有形的指导，但 但这是造就一名成功科学家的必备素质。

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.