The vesicular monoamine transporter-2: an important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse.
The vesicular monoamine transporter-2: an important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse.
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DOI：
10.1016/b978-0-12-420118-7.00002-0
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Dwoskin, Linda P
中科院分区：
文献类型：
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作者：
Nickell, Justin R;Siripurapu, Kiran B;Vartak, Ashish;Crooks, Peter A;Dwoskin, Linda P
甲基苯丙胺滥用升级，但没有批准的治疗方法可用于治疗成瘾的个人。甲基苯丙胺通过与囊泡单胺转运体2(VMAT2)相互作用，抑制多巴胺的摄取，促进突触小泡的多巴胺释放，增加胞内可供多巴胺转运体(DAT)反向转运的多巴胺，从而增加细胞外多巴胺在奖赏相关途径中的作用。VMAT2是我们迭代药物发现努力的目标，以确定治疗甲基苯丙胺成瘾的药物疗法。洛贝林是Lobelia inflata的主要生物碱，能有效抑制VMAT2、甲基苯丙胺诱发的纹状体多巴胺释放和甲基苯丙胺自身给药，但对烟碱型乙酰胆碱受体(NAChRs)有很高的亲和力。去功能化的不饱和洛贝林类似物，中位转二烯(MTD)，在体外表现出洛贝林样的药理作用，缺乏nAChR亲和力，但对DAT有很高的亲和力，提示可能存在滥用倾向。2，4-二氯苯基MTD类似物UKMH-106对VMAT2的选择性优于DAT，可抑制甲基苯丙胺诱发的多巴胺释放，但需要一种困难的合成方法。洛贝兰是一种饱和的去功能化洛贝林类似物，可抑制甲基苯丙胺的神经化学和行为效应；耐受性发展为洛贝兰导致甲基苯丙胺自我给药减少。通过将手性N-1，2-二羟丙基部分掺入洛贝兰得到GZ-793A，从而改善了药物的类似性，GZ-793A抑制了甲基苯丙胺的神经化学和行为影响，没有耐受性。从一系列2，5-二取代吡咯烷类似物中，AV-2-192作为先导出现，对VMAT2表现出高亲和力，并抑制甲基苯丙胺引起的多巴胺释放。目前的结果支持这样一种假设，即有效的、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VMAT2相对于DAT的选择性，作为减少治疗药物滥用倾向的标准。
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.