Tanda Gianluigi, Newman Amy H, Katz Jonathan L
Medications Discovery Research Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.
Adv Pharmacol. 2009;57:253-89. doi: 10.1016/S1054-3589(08)57007-4. Epub 2009 Nov 27.
Stimulant drugs acting at the dopamine transporter (DAT), like cocaine, are widely abused, yet effective medical treatments for this abuse have not been found. Analogs of benztropine (BZT) that, like cocaine, act at the DAT have effects that differ from cocaine and in some situations block the behavioral, neurochemical, and reinforcing actions of cocaine. Neurochemical studies of dopamine levels in brain and behavioral studies have demonstrated that BZT analogs have a relatively slow onset and reduced maximal effects compared to cocaine. Pharmacokinetic studies, however, indicated that the BZT analogs rapidly access the brain at concentrations above their in vitro binding affinities, while binding in vivo demonstrates apparent association rates for BZT analogs lower than that for cocaine. Additionally, the off-target effects of these compounds do not fully explain their differences from cocaine. Initial structure-activity studies indicated that BZT analogs bind to DAT differently from cocaine and these differences have been supported by site-directed mutagenesis studies of the DAT. In addition, BZT analog-mediated inhibition of uptake was more resistant to mutations producing inward conformational DAT changes than cocaine analogs. The BZT analogs have provided new insights into the relation between the molecular and behavioral actions of cocaine and the diversity of effects produced by dopamine transport inhibitors. Novel interactions of BZT analogs with the DAT suggest that these drugs may have a pharmacology that would be useful in their development as treatments for cocaine abuse.
作用于多巴胺转运体（DAT）的兴奋剂药物，如可卡因，被广泛滥用，但尚未找到针对这种滥用的有效医学治疗方法。与可卡因一样作用于DAT的苯托品（BZT）类似物，其效果与可卡因不同，在某些情况下可阻断可卡因的行为、神经化学和强化作用。对大脑中多巴胺水平的神经化学研究和行为研究表明，与可卡因相比，BZT类似物起效相对较慢且最大效应降低。然而，药代动力学研究表明，BZT类似物在浓度高于其体外结合亲和力时能迅速进入大脑，而在体内的结合显示BZT类似物的表观缔合速率低于可卡因。此外，这些化合物的脱靶效应并不能完全解释它们与可卡因的差异。初步的构效关系研究表明，BZT类似物与DAT的结合方式不同于可卡因，定点突变研究也证实了这些差异。此外，与可卡因类似物相比，BZT类似物介导的摄取抑制对产生内向构象DAT变化的突变更具抗性。BZT类似物为可卡因的分子作用与行为作用之间的关系以及多巴胺转运抑制剂产生的效应多样性提供了新的见解。BZT类似物与DAT的新型相互作用表明，这些药物可能具有一种药理学特性，有助于将其开发为可卡因滥用的治疗药物。
