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

项目摘要 没有批准的药物可用于可卡因滥用，阿片类药物成瘾仅限于 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， 最近是因为药物依赖和复发。其中一个最可行的治疗目标， 谷氨酸系统是谷氨酸转运子亚型1（GLT-1），一种主要的星形胶质细胞蛋白， 从CNS的细胞外区室释放谷氨酸。GLT-1转运和摄取机制是 在COC或阿片类药物暴露期间失调，并促进脑中谷氨酸传递的增强 依赖和复发背后的奖赏回路。增强GLT-1表达的药剂 转运蛋白在药物成瘾和相关CNS疾病的临床前模型中确实显示出有效性，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商本身， 主要局限于β-内酰胺类抗生素，这些抗生素存在许多药代动力学和药效学问题， 包括肠胃外给药、脑渗透性差、慢性给药、副作用和缓慢发作 CNS疗效依赖于GLT-1蛋白表达的增加。在本提案中，我们同时解决 可卡因和阿片类药物成瘾缺乏有效的治疗方法，GLT-1激活剂的多样性有限 渠道.我们建议描述两种非β-内酰胺GLT-1激活剂（例如曲瑞鲁唑[TRLZ]）的疗效 和NA-014）在模拟可卡因和阿片样物质强化、依赖性和复发的大鼠测定中。TRLZ是一个 利鲁唑（批准用于ALS）的前药，已经在临床试验中进行了强迫症的测试。 和脊髓小脑。TRLZ显示出独特的药效学特征，因为它的作用是通过 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。尽管 谷氨酸为基础的概况，有利于潜在的治疗药物滥用，母体药物RLZ只 在一些临床前研究中进行了评估，这些研究产生了混合结果。我们对RLZ类化合物的兴趣 最近，2018年的一项研究重新点燃了药物成瘾，该研究表明RLZ可以减少大鼠的可卡因复发。RLZ 然而，它本身是一个不太可能的候选人重新利用，因为降低的功效和效力有关， 药代动力学局限性，包括高首过肝代谢、肝酶升高、阴性 食物效应、低水溶性和差的口服适口性。为了减轻RLZ的限制，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征。 第二个GLT-1激活剂是NA-014，其通过选择性变构调节直接激活GLT-1 GLT-1的单次暴露后，使其不同于β-内酰胺依赖于GLT-1的上调，但 只有在高剂量重复治疗后才能发生。总之，我们的结果将提供第一个全面的 关于非β-内酰胺GLT-1激活剂在药物成瘾临床前模型中的疗效的信息，以及，如果 这可能为开发更安全，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.