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

非 β-内酰胺 GLT-1 激活剂：阿片类药物和可卡因成瘾临床前模型的表征

基本信息

批准号：
10265449
负责人：
SCOTT M. RAWLS
金额：
$ 41.76万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10265449
关键词：
Active Biological Transport Address Adverse effects Affect Agonist Animal Model Antibiotic Resistance Astrocytes Behavioral Biological Assay Biological Markers Brain Brain Ischemia Central Nervous System Diseases Cerebellar Ataxia Chemistry Chronic Clinic Clinical Trials Cocaine Cocaine Abuse Cocaine Dependence Cues Data Development Diarrhea Dose Drug Addiction Drug Kinetics Drug abuse Enhancers Enzymes Female Food GLAST Protein Generations Glutamate Transporter Glutamates In Vitro Intake Intestinal Absorption Investigation Laboratories Link Liver Metabolic Metabolism Methadone Modeling Monobactams Morphine Motor Activity Naloxone Neurological Models Neurons Nucleus Accumbens Obsessive-Compulsive Disorder Opiate Addiction Opioid Oral Outcome Oxycodone Palate Parents Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacotherapy Phase I Clinical Trials Physical Dependence Plasma Pre-Clinical Model Prodrugs Proteins Psychological reinforcement Rattus Relapse Replacement Therapy Rewards Riluzole Safety Schedule Self Administration Solubility Spinal Structure Sucrose System Testing Translations Up-Regulation Withdrawal addiction analog aqueous base beta-Lactams buprenorphine abuse clinical translation cocaine exposure cocaine relapse conditioned place preference dependence relapse design druggable target effective therapy effectiveness testing extracellular gastrointestinal system healthy volunteer improved in vivo in vivo evaluation interest liver metabolism male nervous system disorder neurochemistry opioid exposure painful neuropathy parenteral administration pharmacokinetics and pharmacodynamics pre-clinical preclinical study preference prescription opioid protein expression reuptake therapeutic target transmission process uptake

项目摘要

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.

项目总结