Novel GLT-1 activators for the treatment of alcohol dependence: preclinical studies

用于治疗酒精依赖的新型 GLT-1 激活剂：临床前研究

• 批准号: 10517529
• 负责人: Magid Abou-Gharbia
• 金额: $ 43.7万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517529
• 关键词: Alcohol consumption; Alcohol dependence; Antibiotics; Antiinflammatory Effect; Attenuated; Behavior; Biological Assay; Biological Markers; Brain region; Ceftriaxone; Chemicals; Chronic; Clavulanic Acids; Clinical; Clinical Trials; Cocaine; Consumption; Cystine; Data; Dependence; Development; Dose; Drug Addiction; Drug Kinetics; Effectiveness; Ethanol; Ethanol dependence; Excitatory Amino Acid Transporter 2; FDA approved; Female; Glutamate Transporter; Glutamates; Goals; Homeostasis; In Vitro; Injections; Intake; Lactams; Lead; Link; Lipids; Liver; Medial; Membrane; Monobactams; Neuropharmacology; Nucleus Accumbens; PPAR alpha; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Actions; Pharmacology; Prefrontal Cortex; Procedures; Property; Proteins; Rattus; Relapse; Therapeutic Effect; Up-Regulation; Work; alcohol abuse therapy; alcohol exposure; alcohol preferring rats; alcohol relapse; alcohol seeking behavior; analog; antiporter; attenuation; beta-Hydroxybutyrate; beta-Lactamase; beta-Lactams; brain reward regions; dependence relapse; drinking behavior; drug action; drug of abuse; extracellular; in vivo; inflammatory marker; inhibitor; innovation; lipophilicity; male; neurochemistry; neuroinflammation; neuropsychiatric disorder; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; preclinical study; scaffold; transmission process; uptake

Abstract: Emerging evidence indicates that many aspects of ethanol (EtOH) and drug dependence involve changes in glutamate transmission in central reward brain regions, including the nucleus accumbens and medial prefrontal cortex. Upregulation of glutamate transporter 1 (GLT-1) in these brain regions with i.p. injections of several β-lactams, including ceftriaxone, attenuated EtOH intake and EtOH relapse behaviors in alcohol-preferring rats (P rats). GLT-1 is responsible for the uptake of the majority of extracellular glutamate. In addition, cystine/glutamate exchanger (xCT) is another astroglial protein involved in regulating glutamate homeostasis. The premise of this work is to pursue a very extensive preclinical study that will investigate the neuropharmacology of novel GLT- 1 upregulators, MC-100093, and derivatives as well as a non-antibiotic FDA-approved β-lactam, clavulanic acid (CLAV), which is a β-lactamase inhibitor in both continuous EtOH intake and EtOH relapse behavior. In this study, we will investigate novel -lactams (MC-100093 and derivatives), which do not have antibiotic action, on the expression of GLT-1 and xCT, and anti-inflammatory effects. The experimental goals are: (Aim 1) Investigate the pharmacokinetics.pharmacodynamics and target engagement of MC-100093 and, its derivatives and CLAV to determine dosing, and nominate efficacy biomarkers for subsequent use in P rats; (Aim 2) Investigate the pharmacological mechanisms of action of MC-100093 and its derivatives, and CLAV involving the upregulation of GLT-1 and xCT, and attenuation of neuroinflammation in P rats. Data generated from this project will show that novel drugs can upregulate GLT-1 expression and could have significant clinical implications for alcohol dependence and other neuropsychiatric disorders characterized by the hyperglutamatergic state as well as modulating neuroinflammation associated with an increase in extracellular glutamate in central brain regions that regulate drug dependence; and (Aim 3) to identify optimized, more lipophilic analogs of MC-100093 with drug-like properties and pharmacokinetic profiles that support once-dosing.

摘要： 新出现的证据表明，乙醇(乙醇)和药物依赖的许多方面涉及 中枢奖赏脑区谷氨酸传递的变化，包括核团 伏隔核和内侧前额叶皮质。谷氨酸转运蛋白1(GLT-1)在这些细胞中的表达上调 有IP的脑区。注射几种β-内酰胺类药物，包括头孢曲松，减少乙醇摄入 酒精嗜好大鼠(P鼠)的乙醇复发行为。GLT-1负责摄取 胞外的大部分谷氨酸。此外，胱氨酸/谷氨酸交换器(XCT)是另一种 参与调节谷氨酸动态平衡的星形胶质蛋白。这项工作的前提是 进行非常广泛的临床前研究，研究新型GLT的神经药理学- 1增强剂、MC-100093及其衍生物以及美国食品和药物管理局批准的非抗生素β-内酰胺， 克拉维酸(CLAV)，它是乙醇连续摄入和乙醇中的β-内酰胺酶抑制剂 故态复萌。在本研究中，我们将研究新型-内酰胺(MC-100093及其衍生物)， 无抗菌作用，对GLT-1和XCT的表达有抗炎作用 效果。实验目标是：(1)研究药物动力学。药效学 和MC-100093及其衍生物和CLAV的靶向接合以确定剂量，以及 提名有效性生物标记物以供后续在P鼠身上使用；(目标2)调查 MC-100093及其衍生物的药理作用机制，以及涉及 上调GLT-1和XCT，减轻P大鼠神经炎症。生成的数据 该项目将表明，新药可以上调GLT-1的表达，并可能 酒精依赖和其他神经精神障碍的重要临床意义 以高谷氨酸状态以及调节相关的神经炎症为特征 调节药物依赖的中央脑区域细胞外谷氨酸增加； 和(目标3)确定优化的、更亲油的MC-100093类似物，具有药物性质 以及支持一次给药的药代动力学特征。