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

项目总结 目前还没有批准的可卡因滥用药物，治疗阿片成瘾的药物仅限于 滥用的激动剂替代疗法本身就有责任。谷氨酸是一种神经化学系统， 最近因药物依赖和复发而被捕。最可行的治疗靶点之一 谷氨酸系统是谷氨酸转运体亚型1(GLT-1)，是一种主要的星形细胞蛋白，可以清除 谷氨酸来自中枢神经系统的胞外隔室。GLT-1的转运和摄取机制是 在COC或阿片类药物暴露过程中调节失调，促进谷氨酸在脑内的增强传递 依赖和复发背后的奖赏回路。促进GLT-1表达的药物 转运蛋白在药物成瘾的临床前模型和相关的中枢神经系统疾病中确实显示出疗效，但 现存的障碍是令人失望的临床翻译。问题的一部分是代理本身，它们是 主要限于β-内酰胺类抗生素，这些抗生素存在一系列药代动力学和药效学问题， 包括肠外给药、脑渗透性差、慢性给药、不良反应和起病缓慢。 中枢神经系统的疗效依赖于GLT-1蛋白表达的增加。在这项提案中，我们解决了这两个问题 缺乏治疗可卡因和阿片成瘾的有效方法，以及GLT-1激活剂的多样性有限 输油管道。我们建议对两种非β-内酰胺类GLT-1激动剂(例如曲利鲁唑)的疗效进行表征 和NA-014)在大鼠实验中模拟可卡因和阿片类药物的强化、依赖和复发。TRLZ是一种 利鲁唑前药(批准用于ALS)，已在强迫症的临床试验中进行测试 精神障碍和小脑脊髓炎。TRLZ显示了独特的药效学特征，因为它通过 促进细胞谷氨酸摄取和抑制神经元谷氨酸释放的双重机制。尽管有一个 基于谷氨酸的特征有利于潜在地治疗药物滥用，母药RLZ只有 在少数临床前研究中进行了评估，结果喜忧参半。我们对RLZ类化合物的兴趣 最近，2018年的一项研究表明，RLZ减少了大鼠的可卡因复发，重新点燃了毒瘾。RLZ 然而，它本身不太可能被重新利用，因为与以下相关的效力和效力降低了 药代动力学限制，包括高首过肝代谢率，肝酶升高，阴性 食物效果差，水溶度低，口感差。为了减轻RLZ的限制，我们设计了 合成并评价了体内外优化的第三代前药TRLZ。 第二个GLT-1激活剂是NA-014，它通过选择性变构调节直接激活GLT-1 不同于依赖于GLT-1上调的β-内酰胺类药物，但 只有在反复使用高剂量治疗后才会发生。总而言之，我们的成果将提供第一个全面的 关于非β-内酰胺类GLT-1激动剂在药物成瘾的临床前模型中的有效性的信息，以及，如果 阳性，可能为开发更安全和更有效的基于GLT-1的药物铺平道路。

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.