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.

抽象的： 新兴证据表明乙醇（ETOH）和药物依赖的许多方面涉及 中央奖励大脑区域的谷氨酸传播的变化，包括核 伏尊和媒体前额叶皮层。在这些中的上调谷氨酸转运蛋白1（GLT-1） 带有i.p.的大脑区域注射几种β-内酰胺，包括头孢曲松，减弱EtOH摄入量 和饮酒的大鼠（P大鼠）中的ETOH继电器行为。 GLT-1负责吸收 大多数细胞外谷氨酸。此外，胱氨酸/谷氨酸交换器（XCT）是另一个 星形胶质细胞蛋白参与反思谷氨酸稳态。这项工作的前提是 进行一项非常广泛的临床前研究，该研究将研究新型GLT-的神经药理 1个上调剂，MC-100093和衍生物以及非抗抗生素FDA批准的β-内酰胺， 克拉夫拉酸（CLAV），它是连续EtOH和EtOH中的β-内酰胺酶抑制剂 复发行为。在这项研究中，我们将研究新颖的lactams（MC-100093和衍生物）， 对GLT-1和XCT的表达和抗炎作用没有抗生素作用 效果。实验目标是：（ AIM 1）研究药代动力学。 以及MC-100093及其衍生物和CLAV的目标参与，以确定给药，以及 提名效率生物标志物，以随后在P大鼠中使用； （目标2）调查 MC-100093及其衍生物的作用的药理机制，以及涉及的CLAV GLT-1和XCT的上调，以及P大鼠神经炎症的衰减。生成的数据 从这个项目中将表明新型药物可以更新GLT-1的表达，并且可能有 对酒精依赖性和其他神经精神疾病的临床意义的重要临床意义 以高谷氨酸能态以及调节神经炎症相关的特征 在调节药物依赖性的中央大脑区域中细胞外谷氨酸的增加； （AIM 3）确定具有类似药物的特性的MC-100093的优化，更多的亲脂类似物 和支持一次给药的药代动力学特征。