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:
  • 金额:
    $ 41.76万
  • 依托单位:
  • 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

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

项目成果

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SCOTT M. RAWLS其他文献

SCOTT M. RAWLS的其他文献

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{{ truncateString('SCOTT M. RAWLS', 18)}}的其他基金

Kratom and Cannabinoid Constituents: Mechanisms and Interactive Effects in Neuropathic Pain
卡痛和大麻素成分:神经性疼痛的机制和相互作用
  • 批准号:
    10745835
  • 财政年份:
    2023
  • 资助金额:
    $ 41.76万
  • 项目类别:
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
  • 批准号:
    10417232
  • 财政年份:
    2020
  • 资助金额:
    $ 41.76万
  • 项目类别:
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
  • 批准号:
    10652316
  • 财政年份:
    2020
  • 资助金额:
    $ 41.76万
  • 项目类别:
Therapeutic secrets of kratom alkaloid mitragynine: Testing efficacy in preclinical neuropathic pain and abuse liability models and characterization of underlying opioid and adrenergic mechanisms
卡痛生物碱帽柱木碱的治疗秘密:测试临床前神经性疼痛和滥用倾向模型的功效以及潜在阿片类药物和肾上腺素能机制的表征
  • 批准号:
    9910367
  • 财政年份:
    2019
  • 资助金额:
    $ 41.76万
  • 项目类别:
Chemokine CXCL12/CXCR4 system and synthetic cathinones
趋化因子CXCL12/CXCR4系统和合成卡西酮
  • 批准号:
    10187189
  • 财政年份:
    2018
  • 资助金额:
    $ 41.76万
  • 项目类别:
Chemokine CXCL12/CXCR4 system and synthetic cathinones
趋化因子CXCL12/CXCR4系统和合成卡西酮
  • 批准号:
    9913484
  • 财政年份:
    2018
  • 资助金额:
    $ 41.76万
  • 项目类别:
Chemokine CXCL12/CXCR4 system and synthetic cathinones
趋化因子CXCL12/CXCR4系统和合成卡西酮
  • 批准号:
    10392410
  • 财政年份:
    2018
  • 资助金额:
    $ 41.76万
  • 项目类别:
Psychoactive bath salts and the glutamate system
精神活性浴盐和谷氨酸系统
  • 批准号:
    8862040
  • 财政年份:
    2015
  • 资助金额:
    $ 41.76万
  • 项目类别:
Psychoactive bath salts and the glutamate system
精神活性浴盐和谷氨酸系统
  • 批准号:
    9321202
  • 财政年份:
    2015
  • 资助金额:
    $ 41.76万
  • 项目类别:
Psychoactive bath salts and the glutamate system
精神活性浴盐和谷氨酸系统
  • 批准号:
    9139439
  • 财政年份:
    2015
  • 资助金额:
    $ 41.76万
  • 项目类别:

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