Non-beta-lactam GLT-1 activators: characterization in preclinical models of opioid and cocaine addiction

非 β-内酰胺 GLT-1 激活剂：阿片类药物和可卡因成瘾临床前模型的表征

基本信息

批准号：
10417232
负责人：
SCOTT M. RAWLS
金额：
$ 41.47万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10417232
关键词：
Active Biological Transport Address Adverse effects Affect Agonist Animal Model Antibiotic Resistance Astrocytes Behavioral Biological Assay Biological Markers Brain Brain Ischemia Central Nervous System Diseases Cerebellar Ataxia Chemistry Chronic Clinic Clinical Trials Cocaine Cocaine Abuse Cocaine Dependence Cues Data Development Diarrhea Dose Drug Addiction Drug Kinetics Drug abuse Enhancers Enzymes Female Food GLAST Protein Generations Glutamate Transporter Glutamates In Vitro Intake Intestinal Absorption Investigation Laboratories Link Liver Metabolic Metabolism Methadone Modeling Monobactams Morphine Motor Activity Naloxone Neurological Models Neurons Nucleus Accumbens Obsessive-Compulsive Disorder Opiate Addiction Opioid Oral Outcome Oxycodone Palate Parents Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacotherapy Phase I Clinical Trials Physical Dependence Plasma Pre-Clinical Model Prodrugs Proteins Psychological reinforcement Rattus Relapse Replacement Therapy Rewards Riluzole Safety Schedule Self Administration Solubility Spinal Sucrose System Testing Translations Up-Regulation Withdrawal addiction analog aqueous base beta-Lactams buprenorphine abuse clinical translation cocaine exposure cocaine relapse conditioned place preference dependence relapse design druggable target effective therapy effectiveness testing extracellular gastrointestinal system healthy volunteer improved in vivo in vivo evaluation interest liver metabolism male nervous system disorder neurochemistry opioid exposure painful neuropathy parenteral administration pharmacokinetics and pharmacodynamics pre-clinical preclinical study preference protein expression reuptake therapeutic target transmission process uptake

项目摘要

PROJECT SUMMARY No approved medications are available for cocaine abuse, and medications for opioid addiction are limited to agonist replacement therapies that are abuse liable themselves. Glutamate is one neurochemical system that has been recently for drug dependence and relapse. One of the most viable therapeutic targets within the glutamate system is glutamate transporter subtype 1 (GLT-1), a predominantly astrocytic protein that clears glutamate from the extracellular compartment in the CNS. GLT-1 transport and uptake mechanisms are dysregulated during COC or opioid exposure and facilitate the enhanced glutamate transmission in brain reward circuits that underlie dependence and relapse. Agents that enhance the expression of GLT-1 transporters do display efficacy in preclinical models of drug addiction and related CNS disorders, but an existing hurdle is the disappointing clinical translation. Part of the problem is the agents themselves, which are limited mostly to β-lactam antibiotics that suffer from a host of pharmacokinetic and pharmacodynamic issues, including parenteral administration, poor brain penetrability, chronic dosing, adverse effects, and a slow onset of CNS efficacy that is dependent on increased GLT-1 protein expression. In this proposal, we address both the lack of effective treatments for cocaine and opioid addiction and the limited diversity in the GLT-1 activator pipeline. We propose to characterize the efficacy of two non-β-lactam GLT-1 activators (e.g. troriluzole [TRLZ] and NA-014) in rat assays that model cocaine and opioid reinforcement, dependence, and relapse. TRLZ is a prodrug of riluzole (approved for ALS) that is already being tested in clinical trials for obsessive-compulsive disorder and spinal cerebella. TRLZ displays a unique pharmacodynamic profile in that it acts that acts through a dual mechanism to enhance cellular glutamate uptake and inhibit neuronal glutamate release. Despite a glutamate-based profile that is favorable for potentially treating drug abuse, the parent drug RLZ has only been assessed in few preclinical studies that have yielded mixed outcomes. Our interest in RLZ-like compounds for drug addiction was recently reignited by a 2018 study showing that RLZ reduces cocaine relapse in rats. RLZ itself, however, is an unlikely candidate for repurposing because of reduced efficacy and potency related to pharmacokinetic limitations, including high first-pass hepatic metabolism, elevated liver enzymes, a negative food effect, low aqueous solubility, and poor oral palatability. To mitigate limitations of RLZ, we designed, synthesized, and evaluated TRLZ as a third-generation prodrug with optimized in vitro and in vivo features. The second GLT-1 activator is NA-014, which directly activates GLT-1 through selective allosteric modulation of GLT-1 after a single exposure, making it different from β-lactams that rely on upregulation of the GLT-1 but only after repeated treatment with high doses. In summary, our results will offer the first comprehensive information about the efficacy of non-β-lactam GLT-1 activators in preclinical models of drug addiction, and, if positive, may pave the way for the development of safer and more effective GLT-1-based medications.

项目概要没有批准的药物可用于治疗可卡因滥用，治疗阿片类药物成瘾的药物仅限于激动剂替代疗法本身就容易被滥用，谷氨酸是一种神经化学系统。最近已成为药物依赖和复发的最可行的治疗目标之一。谷氨酸系统是谷氨酸转运蛋白亚型 1 (GLT-1)，一种主要星形胶质细胞蛋白，可清除 GLT-1 的转运和摄取机制是来自 CNS 细胞外区室的谷氨酸。在 COC 或阿片类药物暴露期间失调，促进大脑中谷氨酸传输的增强增强 GLT-1 表达的药物的奖励回路。转运蛋白确实在药物成瘾和相关中枢神经系统疾病的临床前模型中显示出功效，但现有的障碍是令人失望的临床转化，部分问题在于药物本身。主要限于存在许多药代动力学和药效学问题的β-内酰胺抗生素，包括肠胃外给药、脑渗透性差、长期给药、不良反应和起效缓慢 CNS 功效取决于 GLT-1 蛋白表达的增加。在本提案中，我们解决了这两个问题。缺乏针对可卡因和阿片类药物成瘾的有效治疗方法以及 GLT-1 激活剂的多样性有限我们建议表征两种非 β-内酰胺 GLT-1 激活剂（例如曲鲁唑 [TRLZ]）的功效。和 NA-014）在模拟可卡因和阿片类药物强化、依赖性和复发的大鼠试验中是一种。利鲁唑前药（已批准用于 ALS），已在强迫症临床试验中进行测试 TRLZ 表现出独特的药效学特征，因为它通过作用发挥作用。尽管存在增强细胞谷氨酸摄取和抑制神经元谷氨酸释放的双重机制。基于谷氨酸的特征有利于潜在治疗药物滥用，母体药物 RLZ 仅被我们对 RLZ 类化合物的兴趣进行了一些临床前研究的评估，这些研究产生了不同的结果。 2018 年的一项研究最近重新引发了毒瘾，该研究表明 RLZ 可以减少大鼠的可卡因复发。然而，由于与相关的功效和效力降低，其本身不太可能被重新利用药代动力学限制，包括高首过肝代谢、肝酶升高、阴性食物效应、低水溶性和较差的口服适口性为了减轻 RLZ 的局限性，我们设计了，合成并评估 TRLZ 作为第三代前药，具有优化的体外和体内特性。第二种GLT-1激活剂是NA-014，它通过选择性变构调节直接激活GLT-1 单次暴露后 GLT-1 的增加，使其不同于依赖于 GLT-1 上调的 β-内酰胺类药物，但只有经过高剂量的反复治疗后，我们的结果才会提供第一个全面的结果。有关非 β-内酰胺 GLT-1 激活剂在药物成瘾临床前模型中的功效的信息，以及，如果积极的结果可能为开发更安全、更有效的基于 GLT-1 的药物铺平道路。