GLT-1 Enhancers as Drug Candidates for Treating Cocaine Addiction

GLT-1 增强剂作为治疗可卡因成瘾的候选药物

• 批准号: 8673100
• 负责人: Magid Abou-Gharbia
• 金额: $ 50.44万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8673100
• 关键词: Adverse effects; Affect; Animal Model; Animals; Antibiotics; Attenuated; Bacteria; Bioavailable; Biological Availability; Brain; Brain region; Catalytic Domain; Ceftriaxone; Cephalosporins; Characteristics; Chemicals; Chronic; Clinic; Clinical; Cocaine; Cocaine Dependence; Cues; Cysteine; Diarrhea; Dose; Enhancers; Ensure; Extinction (Psychology); Food; Glutamate Transporter; Glutamates; Goals; Half-Life; Homeostasis; Human; In Vitro; Kidney; Lactams; Lead; Medical; Modeling; Motivation; Motor; Motor Activity; Nucleus Accumbens; Oral; Patients; Penetration; Pharmaceutical Preparations; Plasma; Preclinical Drug Evaluation; Preparation; Property; Psychotropic Drugs; Rattus; Relapse; Relative (related person); Running; Scheme; Self Administration; Series; Structure; System; Testing; Training; Translating; Up-Regulation; Withdrawal; addiction; analog; antimicrobial; base; beta-Lactams; design; drug candidate; drug withdrawal; effective therapy; extracellular; improved; in vitro activity; in vivo; intravenous administration; lipophilicity; novel; parenteral administration; pre-clinical; prevent; programs; prospective; protective effect; public health relevance; resistant strain; response; scaffold; screening; success; therapy development; uptake

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.

描述（由申请人提供）：可卡因成瘾仍然是一个严重的未满足的医疗需求，没有真正有效的治疗。 可卡因成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（Ceftriaxone）是一种头孢菌素类抗生素，可增加主要谷氨酸转运体GLT的表达和功能 1（罗斯坦等人，2005）。 头孢曲松还显示可增加xC-系统的活性，该系统将细胞外半胱氨酸交换为细胞内谷氨酸（Lewerenz et al，2009）。 丘脑核中的基础非突触谷氨酸水平在很大程度上受xC-系统控制，其活性的降低是可卡因自我给药后在该脑区观察到的谷氨酸稳态改变的原因 和大鼠的消退训练（Baker等人，2003）。 xC-的催化亚基是xCT，并且我们已经证明，可卡因自身给药后，xCT和GLT-1的表达在丘脑核核心中降低（Knackstedt et al，2010 a）。我们还表明，头孢曲松减弱了线索和可卡因引发的恢复，同时恢复了延髓核核心中xCT和GLT-1的水平（Knackstedt et al，2010 a）。此外，头孢曲松对复发的保护作用在头孢曲松末次给药后持续数周（Sondheimer & Knackstedt，2011）。 虽然头孢曲松作为治疗人类可卡因成瘾的药物显示出临床前前景，但它具有几个可能阻止其从实验室转化为临床的特征。作为抗生素，它具有抗菌活性，因此长期使用 头孢曲松可诱导细菌耐药菌株。在达到治疗上有意义的CNS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，头孢曲松需要胃肠外输注， 可卡因依赖性患者将遵从每日静脉内施用头孢曲松。 我们最近发现了MC-100093，一种来自一系列 单环氮杂环丁酮，作为GLT-1表达的有效上调剂，其是口服生物可利用的，脑渗透剂，并在公认的可卡因成瘾和戒断模型中诱导GLT-1上调。 该提案旨在使用明确定义的筛选方案和多维方法进一步优化MC-100093代表的化学支架，以获得一种或多种可推进IND使能研究的高级先导分子。