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首页> 外文期刊>The European Journal of Neuroscience >Distinct effects of (R)-modafinil and its (R)- and (S)-fluoro-analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats
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Distinct effects of (R)-modafinil and its (R)- and (S)-fluoro-analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats

机译：（r）-modafinil及其（r） - 和（s） - 和（s） - 氟胺类多巴胺对大鼠伏安法和微透析评估

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Psychostimulant use disorders remain an unabated public health concern worldwide, but no FDA approved medications are currently available for treatment. Modafinil (MOD), like cocaine, is a dopamine reuptake inhibitor and one of the few drugs evaluated in clinical trials that has shown promise for the treatment of cocaine or methamphetamine use disorders in some patient subpopulations. Recent structure-activity relationship and preclinical studies on a series of MOD analogs have provided insight into modifications of its chemical structure that may lead to advancements in clinical efficacy. Here, we have tested the effects of the clinically available (R)-enantiomer of MOD on extracellular dopamine levels in the nucleus accumbens shell, a mesolimbic dopaminergic projection field that plays significant roles in various aspects of psychostimulant use disorders, measured in vivo by fast-scan cyclic voltammetry and by microdialysis in Sprague-Dawley rats. We have compared these results with those obtained under identical experimental conditions with two novel and enantiopure bis(F) analogs of MOD, JBG1-048 and JBG1-049. The results show that (R)-modafinil (R-MOD), JBG1-048, and JBG1-049, when administered intravenously with cumulative drug-doses, will block the dopamine transporter and reduce the clearance rate of dopamine, increasing its extracellular levels. Differences among the compounds in their maximum stimulation of dopamine levels, and in their time course of effects were also observed. These data highlight the mechanistic underpinnings of R-MOD and its bis(F) analogs as pharmacological tools to guide the discovery of novel medications to treat psychostimulant use disorders.
机译：精神疗法使用障碍仍然是全球且目前没有FDA批准的药物治疗的未公开的公共卫生问题。 Mocafinil（Mod），如可卡因，是多巴胺再摄取抑制剂，并且在临床试验中评价的少数药物中的一种，这些药物在一些患者群中展示了治疗可卡因或甲基苯丙胺使用障碍的承诺。关于一系列MOD类似物的最近结构 - 活动关系和临床前研究已经为其化学结构的修改提供了深入的洞察力，这可能导致临床疗效的进步。在这里，我们已经测试了Mod的临床可用（R） - 蒽酰胺对细胞核壳体的细胞外多巴胺水平的影响，叶霉素多巴胺能投影场在精神潜能使用障碍的各个方面起着显着的作用，通过快速测量-Scan循环伏安法和Sprague-Dawley大鼠的微透析。我们已经将这些结果与在相同的实验条件下获得的结果进行了比较，其中Mod，JBG1-048和JBG1-049的两种新颖和对映对BIS（F）类似物。结果表明（R）-Modafinil（R-Mod），JBG1-048和JBG1-049静脉内施用累积药物剂量，将阻断多巴胺转运蛋白，降低多巴胺的间隙，增加其细胞外水平。还观察到化合物在其最大刺激多巴胺水平中的差异，以及在其时间的效果过程中。这些数据突出R-MOD和其双（F）作为类似物的药理学工具的机械基础来指导新药物的发现来治疗精神兴奋剂使用障碍。

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