Characterization, optimization, and development of dual mGlu2/3 positive allosteric modulators for opioid use disorder

项目摘要 阿片类药物使用障碍（OUD）是世界范围内的一个重大问题，甲基苯丙胺（MA）使用的激增使 出现在慢性阿片类药物使用者中。鉴于最近共同滥用的增加，迫切需要新的治疗方法 预防OUD和MA使用障碍（MUD）复发的策略。长期药物暴露 诱导增强的谷氨酸（Glu）介导的突触可塑性，这是过度的生理和 对药物相关线索的行为反应阿片样物质和MA暴露也激活小胶质细胞和星形胶质细胞， 促进促炎细胞因子的释放。所有这些因素都增加了吸毒复发的风险。 由慢性药物使用引起的异常Glu活性的正常化代表了一种新的治疗策略， 预防OUD/MUD复发。代谢型Glu受体亚型2和3（mGlu 2/3）的活化， 激动剂或正变构调节剂（PAM）减少精神兴奋剂的自我给药（SA）以及 提示诱导的恢复（RI）。此外，临床前研究表明，mGlu 2/3激活具有 有望治疗人类压力和焦虑相关疾病，并能系统地增加睡眠。 然而，mGlu 2相对于mGlu 3活化对治疗OUD/MUD的相对贡献尚不清楚。 突触前mGlu 2自身受体的激活导致细胞核中Glu释放的下游抑制 利多卡因，这反过来又减弱了药物RI。此外，在细胞中高度表达的mGlu 3的激活， 星形胶质细胞，导致抗炎细胞因子转化生长因子β（TGF-β）的释放。的 mGlu 2和mGlu 3受体的特异性定位和信号转导导致我们的总体假设 mGlu 2和mGlu 3的双重激活将为OUD和MUD的治疗提供明显的优势 mGlu 2单独激活。我们最近合成并表征了SBI-0799220，一种PAM， 本发明提供了一种对mGlu 2和mGlu 3的效能以及SBI-0801315（一种对mGlu 2相对于mGlu 3具有>50倍选择性的PAM）的方法。初步 数据表明，SBI-0801315减弱氧提示诱导的RI和SA，SBI-0799220减弱MA SA.然而，在OUD和MUD模型中mGlu 2/3与mGlu 2 PAM的直接比较尚未被证实。 进行。本申请的目的是推进mGlu 2/3 PAM作为预防复发的新型治疗 OUD，检查其治疗MUD的潜力，并同时优化mGlu 2/3 PAM。我们将确定 mGlu 2/3和mGlu 2-偏好性PAM减弱Oxy/MA SA和RI、Oxy/MA诱导的 戒断、MA诱导的神经炎症和阿片类药物诱导的大鼠抗伤害感受。同时，我们将 优化我们的mGlu 2/3 PAM系列的药理学和药学特性，包括吸收， 分布、代谢、排泄和药代动力学。我们组建了一个多学科的团队， 研究人员拥有实现这些结果的知识和经验。成功完成这些 研究将加速开发一种新型mGlu 2/3 PAM，以实现研究性新药（IND）， 研究，并最终，一种新的治疗方法，以防止复发的OUD。

PROJECT SUMMARY Opioid Use Disorder (OUD) is a significant problem worldwide and a surge in methamphetamine (MA) use has emerged in chronic opioid users. Given recent increases in co-abuse, there is a dire need for novel treatment strategies that prevent relapse to drug use in both OUD and MA Use Disorder (MUD). Long-term drug exposure induces enhanced glutamate (Glu)-mediated synaptic plasticity, which underlies excessive physiological and behavioral responses to drug-related cues. Opioid and MA exposure also activate microglia and astrocytes, promoting release of pro-inflammatory cytokines. All these factors increase the risk of relapse to drug use. Normalization of aberrant Glu activity caused by chronic drug use represents a novel therapeutic strategy to prevent relapse in OUD/MUD. The activation of metabotropic Glu receptor subtypes 2 and 3 (mGlu2/3) using agonists or positive allosteric modulators (PAMs) decreases psychostimulant self-administration (SA) as well as cue-induced reinstatement (RI) in animals. Moreover, preclinical studies indicate that mGlu2/3 activation has promise for treating stress- and anxiety-related disorders in humans and can systematically augment sleep. However, the relative contribution of mGlu2 versus mGlu3 activation for treating OUD/MUD is not yet known. Activation of presynaptic mGlu2 autoreceptors results in downstream inhibition of Glu release in the nucleus accumbens, which in turn attenuates drug RI. In addition, activation of mGlu3, which is highly expressed in astrocytes, leads to the release of the anti-inflammatory cytokine transforming growth factor beta (TGF-β). The specific localization and signal transduction of mGlu2 and mGlu3 receptors lead to our overarching hypothesis that dual activation of both mGlu2 and mGlu3 will provide a clear advantage for the treatment for OUD and MUD over mGlu2 activation alone. We have recently synthesized and characterized SBI-0799220, a PAM with equal potency for mGlu2 and mGlu3 and SBI-0801315, a PAM with >50-fold selectivity for mGlu2 vs mGlu3. Preliminary data indicate that SBI-0801315 attenuates Oxy cue-induced RI and SA, and that SBI-0799220 attenuates MA SA. However, a direct comparison of mGlu2/3 with mGlu2 PAMs in models of OUD and MUD has not yet been conducted. The goal of this application is to advance mGlu2/3 PAMs as a novel treatment for preventing relapse to OUD, examine their potential for treating MUD, and simultaneously optimize mGlu2/3 PAMs. We will determine the in vivo efficacy of mGlu2/3 and mGlu2-preferring PAMs to attenuate Oxy/MA SA and RI, Oxy/MA-induced withdrawal, MA-induced neuroinflammation, and opioid-induced antinociception in rats. Simultaneously, we will optimize the pharmacological and pharmaceutical properties of our mGlu2/3 PAM series including absorption, distribution, metabolism, excretion, and pharmacokinetics. We have assembled a multidisciplinary team of investigators that has the knowledge and experience to achieve these outcomes. Successful completion of these studies will expedite development of a novel mGlu2/3 PAM towards investigational new drug (IND)-enabling studies and ultimately, a novel treatment for preventing relapse in OUD.