Evaluation of the therapeutic potential of exclusive antagonists of extrasynaptic NMDA receptors for the treatment of opioid use disorder

项目摘要 阿片类药物在美国的使用多年来一直处于流行病的比例。协调努力在 迄今为止，政治、社会意识、临床和研究举措的范围都无法遏制 美国阿片类药物使用率和阿片类药物过量死亡率上升。从治疗的角度来看， 缓解严重阿片类药物戒断症状和/或降低复发风险的新型疗法继续出现， 被提议。对潜在疗法的研究的很大一部分集中在测试FDA批准的药物上 作为阿片类药物使用的潜在治疗方法。这种方法依赖于经过验证的科学原理和临床 验证药物靶点，以确保这些研究将产生有效的阿片类药物使用障碍的新药。 其中一种药物是美金刚胺，一种NMDA受体拮抗剂，作为一种抗抑郁药， 辅助现有的阿片类药物使用疗法。美金刚的治疗作用是由于涉及 阿片类药物成瘾的发展和维持中的阿片能途径及其临床耐受性可能 源于位于突触外的NMDA受体的优先抑制， 受体拮抗剂与严重的临床副作用有关。然而，美金刚浓度必须 保持低水平以利用其优先拮抗作用，因为在较高的（和更有治疗意义的） 相关浓度），美金刚可抑制突触NMDA受体并引发副作用。 为了解决这个问题，NeurANO Bioscience创建了基于纳米颗粒（AuM）的缀合物，其包含： 几个美金刚分子由于其尺寸，AuM不能进入突触间隙和突触NMDA 受体，但允许激活突触外NMDAR受体的效力大大超过 免费美金刚。在I期研究中，我们发现AuM可以大大减少阿片类药物戒断 症状，并证明AuM可以在治疗浓度下递送到大脑中， 鼻内给药。在拟议的第二阶段研究中，我们将继续努力， AuM的商业可制造性，确定最佳给药途径和AuM剂量， 治疗阿片类药物戒断症状，并探索AuM治疗潜力， 获得阿片类药物依赖和/或复发。利用第二阶段研究期间获得的数据，我们将 制定有效的策略，以进行IND使能研究，以使用突触外受体拮抗剂 NMDAR在治疗OUD中的应用

PROJECT SUMMARY Opioid use in the United States has been at epidemic proportions for many years. Concerted efforts across the spectrum of political, social awareness, clinical and research initiatives have so far been unable to curb the rising rates of opioid use and opioid overdose deaths across the USA. From the treatment standpoint, a number of novel therapies to alleviate the severe opioid withdrawal symptoms and/or reduce risk of relapse continue to be proposed. A significant portion of research into potential therapies focuses on testing FDA-approved drugs as potential treatments for opioid use. Such approach relies on the verified scientific rationale and clinically validated drug targets to ensure that these studies will produce efficacious new drugs for opioid use disorder. One of such drugs is memantine, an NMDA receptor antagonist, that has shown encouraging results as an adjunct to existing opioid use therapies. Therapeutics effects of memantine are due to the involvement of glutamatergic pathways in the development and maintenance of opioid addiction, and its clinical tolerability likely derives from preferential inhibition of NMDA receptors located outside the synapse, since broad spectrum NMDA receptor antagonists are associated with serious clinical side effects. However, memantine concentrations must be kept low to take advantage of its preferential antagonism, because at higher (and more therapeutically relevant) concentrations, memantine may inhibit synaptic NMDA receptors and trigger side effects. To resolve this problem, NeurANO Bioscience created a nanoparticle-based (AuM) conjugate comprising several memantine molecules. Due to its dimensions, AuM cannot access the synaptic cleft and synaptic NMDA receptors, but allows activation of extrasynaptic NMDAR receptors with the potency greatly exceeding that of free memantine. During Phase I studies, we discovered that AuM can drastically minimize the opioid withdrawal symptoms, and demonstrated that AuM can be delivered into the brain at therapeutic concentrations using intranasal administration. During proposed Phase II studies, we will proceed with efforts directed at establishing the commercial manufacturability of AuM, determining optimal administration routes and AuM dosage for the treatment of opioid withdrawal symptoms, and exploring AuM therapeutic potential for the prevention of acquisition of opioid dependence and/or relapse. Using the data acquired during Phase II studies, we will develop the efficient strategy to pursue IND-enabling studies for use of exclusive antagonists of extrasynaptic NMDARs in the treatment of OUD.