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The Vesicular Monoamine Transporter-2: An Important Pharmacological Target for the Discovery of Novel Therapeutics to Treat Methamphetamine Abuse

机译：囊泡单胺转运蛋白-2：一种重要的药理靶标用于发现治疗甲基苯丙胺滥用的新型疗法

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Methamphetamine abuse escalates, but no approved therapeutics are available to treat addicted individuals. Methamphetamine increases extracellular dopamine in reward-relevant pathways by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT). VMAT2 is the target of our iterative drug discovery efforts to identify pharmacotherapeutics for methamphetamine addiction. Lobeline, the major alkaloid in Lobelia inflata, potently inhibited VMAT2, methamphetamine-evoked striatal dopamine release, and methamphetamine self-administration in rats but exhibited high affinity for nicotinic acetylcholine receptors (nAChRs). Defunctionalized, unsaturated lobeline analog, meso-transdiene (MTD), exhibited lobeline-like in vitro pharmacology, lacked nAChR affinity, but exhibited high affinity for DAT, suggesting potential abuse liability. The 2,4-dicholorophenyl MTD analog, UKMH-106, exhibited selectivity for VMAT2 over DAT, inhibited methamphetamine-evoked dopamine release, but required a difficult synthetic approach. Lobelane, a saturated, defunctionalized lobeline analog, inhibited the neurochemical and behavioral effects of methamphetamine; tolerance developed to the lobelane-induced decrease in methamphetamine self-administration. Improved drug-likeness was afforded by the incorporation of a chiral N-1,2-dihydroxypropyl moiety into lobelane to afford GZ-793A, which inhibited the neurochemical and behavioral effects of methamphetamine, without tolerance. From a series of 2,5-disubstituted pyrrolidine analogs, AV-2-192 emerged as a lead, exhibiting high affinity for VMAT2 and inhibiting methamphetamine-evoked dopamine release. Current results support the hypothesis that potent, selective VMAT2 inhibitors provide the requisite preclinical behavioral profile for evaluation as pharmacotherapeutics for methamphetamine abuse and emphasize selectivity for VMAT2 relative to DAT as a criterion for reducing abuse liability of the therapeutic.
机译：甲基苯丙胺滥用逐步升级，但尚无批准的疗法可用于治疗成瘾者。甲基苯丙胺通过与水泡单胺转运蛋白2（VMAT2）相互作用来抑制多巴胺摄取并促进多巴胺从突触小泡中释放，增加可用于多巴胺转运蛋白（DAT）逆向转运的胞浆多巴胺，从而增加了奖励相关途径中的细胞外多巴胺。 VMAT2是我们反复进行药物发现工作的目标，以鉴定用于甲基苯丙胺成瘾的药物治疗剂。 Lobeia inflata中的主要生物碱Lobeline在大鼠中有效抑制VMAT2，甲基苯丙胺引起的纹状体多巴胺释放和甲基苯丙胺自我给药，但对烟碱化乙酰胆碱受体（nAChRs）具有高亲和力。去官能化的，不饱和的卵磷脂类似物，中反二烯（MTD）表现出类似于卵磷脂的体外药理学，缺乏nAChR亲和力，但对DAT表现出高亲和力，表明潜在的滥用责任。 2,4-二氯苯并苯基MTD类似物UKMH-106，对VMAT2的选择性优于DAT，抑制了甲基苯丙胺引起的多巴胺的释放，但需要困难的合成方法。 Lobelane，一种饱和的，去功能化的lobeline类似物，可抑制甲基苯丙胺的神经化学和行为作用。对氯苯丙胺引起的甲基苯丙胺自我给药减少的耐受性增强。通过将手性N-1,2-二羟丙基部分掺入洛贝烷中，可提供改善的药物似性，从而提供GZ-793A，其抑制了甲基苯丙胺的神经化学和行为作用，而没有耐受性。从一系列2，5-二取代的吡咯烷类似物中，AV-2-192以铅的形式出现，对VMAT2具有高亲和力，并抑制了甲基苯丙胺诱发的多巴胺释放。目前的结果支持以下假设：有效的，选择性的VMAT2抑制剂为评估甲基苯丙胺滥用的药物治疗提供了必要的临床前行为特征，并强调了相对于DAT的VMAT2选择性，以此作为减少治疗药物滥用责任的标准。

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