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.

项目概要 阿片类药物使用障碍 (OUD) 是一个全球性的严重问题，甲基苯丙胺 (MA) 使用量的激增导致 鉴于最近共同滥用的情况有所增加，迫切需要新的治疗方法。 预防 OUD 和 MA 使用障碍 (MUD) 长期药物暴露复发的策略。 诱导增强的谷氨酸 (Glu) 介导的突触可塑性，这是过度生理和 对阿片类药物和 MA 暴露的行为反应也会激活小胶质细胞和星形胶质细胞， 所有这些因素都会增加促炎细胞因子的释放。 长期吸毒引起的异常 Glu 活性的正常化代表了一种新的治疗策略 使用代谢型 Glu 受体亚型 2 和 3 (mGlu2/3) 的激活来预防 OUD/MUD 复发。 激动剂或正变构调节剂（PAM）会降低精神兴奋剂的自我给药（SA）以及 此外，临床前研究表明 mGlu2/3 激活具有动物体内的提示诱导恢复 (RI)。 有望治疗人类与压力和焦虑相关的疾病，并可以系统地增强睡眠。 然而，mGlu2 与 mGlu3 激活对于治疗 OUD/MUD 的相对贡献尚不清楚。 突触前 mGlu2 自身受体的激活导致下游细胞核中 Glu 释放的抑制 伏隔核，进而减弱药物 RI 此外，mGlu3 的激活，mGlu3 在体内高度表达。 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 受体的特异性定位和信号转导得出了我们的总体假设 mGlu2 和 mGlu3 的双重激活将为 OUD 和 MUD 的治疗提供明显的优势 我们最近合成并表征了 SBI-0799220，这是一种具有同等功能的 PAM。 mGlu2 和 mGlu3 以及 SBI-0801315 的效力，SBI-0801315 是一种对 mGlu2 的选择性比初步的 mGlu3 强 50 倍的 PAM。 数据表明，SBI-0801315 减弱氧提示诱导的 RI 和 SA，而 SBI-0799220 减弱 MA 然而，尚未在 OUD 和 MUD 模型中对 mGlu2/3 与 mGlu2 PAM 进行直接比较。 这项应用的目标是推动 mGlu2/3 PAM 作为预防复发的新型治疗方法。 我们将确定 OUD，检查其治疗 MUD 的潜力，并同时优化 mGlu2/3 PAM。 mGlu2/3 和 mGlu2 偏好的 PAM 减弱 Oxy/MA SA 和 RI、Oxy/MA 诱导的体内功效 同时，我们将在大鼠中进行戒断、MA 诱导的神经炎症和阿片类药物诱导的抗镇痛作用。 优化我们的 mGlu2/3 PAM 系列的药理和药物特性，包括吸收、 我们组建了一个多学科团队。 具有成功完成这些成果的知识和经验的研究人员。 研究将加快新型 mGlu2/3 PAM 的开发，以实现新药研究 (IND) 研究并最终开发出一种预防 OUD 复发的新疗法。