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

项目总结/摘要 我们正在经历第三波鸦片制剂，转向强大的合成药物，这反映在其他滥用药物， 如大麻素（香料）和卡西酮（'浴盐'）。由于经济原因，这些强效药物受到经销商的青睐， 许多新的合成阿片类药物与其靶受体结合得如此紧密，以至于目前的治疗（纳洛酮/纳洛酮） 阿片类药物过量也是无效的有警方报告称，合成阿片类药物过量的受害者被发现与多个 纳洛酮剂量增加或需要IV给药的患者。在芬太尼相关的“木胸综合征”的情况下， 即使是受过训练的心肺复苏术提供者也不能防止窒息死亡。一个有竞争力的对手 负变构调节剂卡芬太尼可能会成功。这些分子通过受体上的次级位点起作用。两 候选化合物已被确定;我们假设μ阿片受体的负变构调节剂 （µORs）可以作为克服强效合成阿片类药物的替代策略，其目标是减轻 阿片类药物毒性该项目涉及这些候选负变构的结构类似物的一系列迭代测试。 调节剂在体外和体内逆转阿片信号传导的能力。我们的目标是开发一个优化的底片 在紧急情况下逆转阿片类药物过量的变构调节剂。由于变构的性质， 调节剂，有理由期待这也将避免纳洛酮引起的强烈戒断症状， 这在紧急情况下也是一个优势。这样的化合物还可以具有上级的 在美沙酮/丁丙诺啡不可用的地方，纳洛酮的药理特性。与当前 在阿片类药物危机的气候下，探索负变构调节剂的影响至关重要，因为它可能导致 一种替代解毒剂，以对抗日益强大的鸦片制剂。 印第安纳州大学是一所大型大学，在生物学研究方面具有优势，特别是在滥用药物方面，如 大麻素和鸦片制剂;该大学还拥有许多支持研究的科学资源（如核心设施）。 神经科学计划是高度互动的，部分原因是吉尔中心赞助了一年一度的研讨会，参观 演讲者和一个杂志俱乐部。制定了一项培训计划，涵盖技术（体外和体内测定）， 课程作业，负责任的研究行为培训，以及一些不太有形的导师，但 但这些都是成功科学家必备的素质。

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.