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

• 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
• 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

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.

项目摘要 没有可卡因滥用的批准药物，阿片类药物成瘾的药物仅限于 痛苦的替代疗法本身是虐待的。谷氨酸是一种神经化学系统 最近已经为毒品依赖和救济而进行。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），一种主要的星形胶质细胞蛋白 来自中枢神经系统的细胞外室的谷氨酸。 GLT-1传输和吸收机制是 在COC或阿片类药物暴露期间失调并支持大脑中增强的谷氨酸传播 奖励依赖和宽慰的电路。增强GLT-1表达的代理 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表现出效率，但是 现有的障碍是令人失望的临床翻译。问题的一部分是代理人本身， 主要限于β-内酰胺抗生素，这些抗生素患有许多药代动力学和药效学问题， 包括父母的给药，脑力不佳，慢性剂量，不良反应和缓慢的发作 CNS效率取决于GLT-1蛋白表达的增加。在此提案中，我们解决了这两个 缺乏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 管道。我们建议表征两个非β-内酰胺GLT-1激活剂的效率（例如，troriluzole [trlz] 和NA-014）在大鼠测定中，对可卡因和阿片类药物的增强，依赖性和救济进行了建模。 trlz是一个 Riluzole（已批准为ALS），该前药已经在临床试验中进行了强迫性强迫症的测试 疾病和脊柱小脑。 TRLZ显示出独特的药效学概况，因为它的作用是通过 一种双重机制，可增强细胞谷氨酸摄取并抑制神经谷氨酸释放。尽管有 基于谷氨酸的概况有利于潜在治疗药物滥用，父级药物RLZ仅是 在少数临床前研究中评估，这些研究产生了混合的结果。我们对类似RLZ的化合物的兴趣 最近，一项2018年的一项研究表明，RLZ减少了大鼠可卡因的缓解。 RLZ 但是，由于与 药代动力学的局限性，包括高第一级肝肝代谢，肝酶升高，阴性 食物效应，低水溶性和口服不良性。为了减轻RLZ的限制，我们设计了 合成并评估了TRLZ作为第三代前药，具有优化的体外和体内特征。 第二个GLT-1激活剂是NA-014，它通过选择性变构调制直接激活GLT-1 一次暴露后的GLT-1，使其与依赖GLT-1上调但 仅在高剂量重复治疗后。总而言之，我们的结果将提供第一个综合 有关非β-内酰胺GLT-1激活剂在药物成瘾模型中的效率的信息，如果 积极，可能为开发更安全，更有效的基于GLT-1的药物铺平道路。