GLT-1 Enhancers as Drug Candidates for Treating Cocaine Addiction

描述(由申请人提供)：可卡因成瘾仍然是一个严重的未得到满足的医疗需求，没有真正有效的治疗方法。对可卡因的上瘾和停药后的复发与中枢神经系统谷氨酸水平和体内平衡的变化有关。研究表明，头孢曲松是一种头孢菌素类抗生素，它能增加主要谷氨酸转运体GLT的表达和功能 1(Rothstein等人，2005年)。头孢曲松还被证明可以增加XC-系统的活性，该系统将细胞外的半胱氨酸交换为细胞内的谷氨酸(Louerenz等人，2009年)。伏隔核内基础的非突触谷氨酸水平主要由XC-系统控制，其活性的降低是可卡因给药后该脑区谷氨酸稳态改变的原因。 和大鼠的消退训练(Baker等人，2003年)。XC-的催化亚基是XCT，我们已经证明了可卡因自我给药后XCT和GLT-1在伏隔核核心的表达减少(Knackstedt等人，2010a)。我们还表明，头孢曲松减弱了线索和可卡因诱导的恢复，同时恢复了伏隔核核心XCT和GLT-1的水平(Knackstedt等人，2010a)。此外，在最后一次注射头孢曲松后，头孢曲松预防复发的保护作用持续数周(Sondheimer&Knackstedt，2011)。虽然头孢曲松显示出作为治疗人类可卡因成瘾的药物的临床前前景，但它具有几个特点，可能会阻止它从试验台上转移到临床上。作为一种抗生素，它具有抗菌活性，因此长期使用 头孢曲松可诱导耐药菌株。在达到具有治疗意义的中枢神经系统浓度所需的高剂量下(由于头孢曲松的低脑生物利用度)，慢性头孢曲松可能会产生不良副作用，如腹泻。此外，头孢曲松需要静脉输液，而且不太可能 可卡因依赖患者将遵守每日静脉注射头孢曲松。我们最近发现了MC-100093，它是一种铅分子，来自一系列 单环氮杂二酮，作为一种强有力的GLT-1表达上调因子，具有口服生物利用度、脑渗透性，并在可卡因成瘾和戒断的公认模型中诱导GLT-1上调。这项提议旨在进一步优化以MC-100093为代表的化学支架，使用定义明确的筛选方案和多维方法来获得一个或多个先进的铅分子，这些分子可以推进到支持IND的研究中。

DESCRIPTION (provided by applicant): Addiction to cocaine remains a serious unmet medical need for which there is no truly effective treatment. Addiction to cocaine an relapse following withdrawal of the drug are associated with changes in CNS glutamate levels and homeostasis. It has been demonstrated that Ceftriaxone, a cephalosporin antibiotic, increases the expression and function of the major glutamate transporter GLT 1 (Rothstein et al, 2005). Ceftriaxone has also been shown to increase the activity of system xC-, which exchanges extracellular cysteine for intracellular glutamate (Lewerenz et al, 2009). Basal non-synaptic glutamate levels in the nucleus accumbens are largely controlled by system xC-, and a decrease in its activity is the cause of the altered glutamate homeostasis observed in this brain region following cocaine self-administration and extinction training in rats (Baker et al, 2003). The catalytic subunit of xC- is xCT, and we have demonstrated that expression of xCT and GLT-1 are decreased in the nucleus accumbens core following cocaine self- administration (Knackstedt et al, 2010a). We have also shown that Ceftriaxone attenuates cue- and cocaine- primed reinstatement while restoring levels of both xCT and GLT-1 in the nucleus accumbens core (Knackstedt et al, 2010a). Furthermore, the protective effect of Ceftriaxone against relapse lasts for weeks following the last administration of Ceftriaxone (Sondheimer & Knackstedt, 2011). While Ceftriaxone shows preclinical promise as a medication for the treatment of cocaine addiction in humans, it possesses several characteristics that may prevent it from translating from the bench to the clinic. As an antibiotic, it possesses antimicrobial activity and thus chronic use of ceftriaxone can induce resistant strains of bacteria. At the high doses required to achieve therapeutically meaningful CNS concentrations (due to Ceftriaxone's low brain bioavailability), chronic Ceftriaxone will likely produce undesirable side effects such a diarrhea. Additionally, Ceftriaxone requires parenteral infusion and it is unlikely that cocaine dependent-patients would comply with daily intravenous administration of Ceftriaxone. We have recently identified MC-100093, a lead molecule from a series of monocyclic azetadinones, as a potent up-regulator of GLT-1 expression that is orally bioavailable, brain penetrant, and induces GLT-1 up-regulation in an accepted model of cocaine addiction and withdrawal. This proposal aims to further optimize the chemical scaffold represented by MC-100093 using a well-defined screening scheme and a multidimensional approach to arrive at one or more advanced lead molecules that can be advanced to IND-enabling studies.