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

用于阿片类药物使用障碍的双 mGlu2/3 正变构调节剂的表征、优化和开发

• 批准号: 10544440
• 负责人: Nicholas David Cosford
• 金额: $ 644.52万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544440
• 关键词: Abstinence; Agonist; Amygdaloid structure; Animals; Anti-Inflammatory Agents; Astrocytes; Attenuated; Autoreceptors; Behavior; Brain region; Chronic; Corpus striatum structure; Cues; Data; Development; Disease; Drug Exposure; Drug Kinetics; Drug usage; Equilibrium; Excretory function; Extinction (Psychology); Glutamates; Goals; Hippocampus (Brain); Homeostasis; Human; Inflammatory; Institutes; Investigational Drugs; Knowledge; Lead; Mediating; Medical; Metabolism; Metabotropic Glutamate Receptors; Methamphetamine; Methamphetamine use disorder; Microglia; Modeling; Neurons; Nucleus Accumbens; Opioid; Opioid Analgesics; Outcome; Oxycodone; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Physiological; Play; Prefrontal Cortex; Property; Rattus; Relapse; Research Personnel; Self Administration; Series; Signal Transduction; Sleep; Sleep disturbances; Stress; Substance Use Disorder; Symptoms; Synapses; Synaptic plasticity; System; Thalamic structure; Therapeutic; Transforming Growth Factor beta; Universities; Withdrawal; Withdrawal Symptom; absorption; anxiety-related disorders; attenuation; base; behavioral response; cytokine; drug seeking behavior; experience; forest; in vivo; methamphetamine exposure; methamphetamine use; multidisciplinary; neuroinflammation; new therapeutic target; non-opioid analgesic; novel; novel therapeutic intervention; opioid abuse; opioid epidemic; opioid exposure; opioid use disorder; opioid user; opioid withdrawal; overdose death; positive allosteric modulator; pre-clinical; preclinical study; prescription opioid; presynaptic; prevent; psychostimulant; receptor; recruit; relapse risk; response; stem; treatment strategy

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.

项目摘要 阿片类药物使用障碍（OUD）在全球范围内是一个重大问题，甲基苯丙胺（MA）的使用激增 出现在慢性阿片类药物用户中。鉴于最近增加的增加，需要新颖的治疗 防止在OUD和MA使用障碍（MUD）中使用药物使用的策略。长期药物暴露 诱导增强的谷氨酸（GLU）介导的合成可塑性，这是超级生理和 行为对与药物有关的提示的反应。阿片类药物和MA暴露还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。所有这些因素增加了退休毒品使用的风险。 慢性药物使用引起的异常GLU活性的归一化代表了一种新型的治疗策略 防止在Oud/Mud中继电器。使用代谢性GLU受体亚型2和3（MGLU2/3）的激活 激动剂或阳性变构调节剂（PAM）降低了精神刺激的自我管理（SA）以及 提示引起的动物恢复（RI）。此外，临床前研究表明MGLU2/3激活具有 有望治疗人类中与压力和动画有关的疾病，并可以系统地增加睡眠。 但是，尚不清楚MGLU2与MGLU3激活对治疗Oud/Mud的相对贡献。 突触前MGLU2自身受体的激活导致核中GLU释放的下游抑制 伏anc，进而减轻药物RI。另外，MGLU3的激活在高度表达 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。 MGLU2和MGLU3受体的特定定位和信号转导导致我们的总体假设 MGLU2和MGLU3的双重激活将为Oud和Mud的处理提供明显的优势 仅在MGLU2激活上。我们最近合成并表征了SBI-0799220 MGLU2和MGLU3和SBI-0801315的效力，MGLU2与MGLU3的PAM具有> 50倍的选择性。初步的 数据表明SBI-0801315减弱了氧提示引起的RI和SA，并且SBI-0799220减弱MA SA。但是，在Oud和Mud模型中，MGLU2/3与MGLU2 PAM的直接比较尚未是 实施。该应用的目的是推进MGLU2/3 PAM作为防止继电器的新方法 为了oud，请检查其治疗泥浆的潜力，并简单地优化MGLU2/3 PAM。我们将确定 MGLU2/3和MGLU2优先pAM的体内效率减弱氧气/MA SA和RI，氧/MA诱导 戒断，MA诱导的神经炎症和OIOID诱导的大鼠抗伤害感受。同时，我们会的 优化我们的MGLU2/3 PAM系列的药物和药物特性，包括滥用， 分布，代谢，排泄和药代动力学。我们组建了一个多学科团队 具有实现这些结果的知识和经验的调查人员。这些成功完成 研究将加快开发新型的MGLU2/3 PAM朝向研究新药（IND）增强 研究并最终是一种用于预防OUD中继的新型治疗方法。