Newman Amy Hauck, Kulkarni Santosh
Medicinal Chemistry Section, National Institute on Drug Abuse--Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
Med Res Rev. 2002 Sep;22(5):429-64. doi: 10.1002/med.10014.
In an attempt to discover a cocaine-abuse pharmacotherapeutic, extensive investigation has been directed toward elucidating the molecular mechanisms underlying the reinforcing effects of this psychostimulant drug. The results of these studies have been consistent with the inhibition of dopamine uptake, at the dopamine transporter (DAT), which results in a rapid and excessive accumulation of extracellular dopamine in the synapse as being the mechanism primarily responsible for the locomotor stimulant actions of cocaine. Nevertheless, investigation of the serotonin (SERT) and norepinephrine (NET) transporters, as well as other receptor systems, with which cocaine either directly or indirectly interacts, has suggested that the DAT is not solely responsible for the reinforcing effects of cocaine. In an attempt to further elucidate the roles of these systems in the reinforcing effects of cocaine, selective molecular probes, in the form of drug molecules, have been designed, synthesized, and characterized. Many of these compounds bind potently and selectively to the DAT, block dopamine reuptake, and are behaviorally cocaine-like in animal models of psychostimulant abuse. However, there have been exceptions noted in several classes of dopamine uptake inhibitors that demonstrate behavioral profiles that are distinctive from cocaine. Structure-activity relationships between chemically diverse dopamine uptake inhibitors have suggested that different binding interactions, at the molecular level on the DAT, as well as divergent actions at the other monoamine transporters may be related to the differing pharmacological actions of these compounds, in vivo. These studies suggest that novel dopamine uptake inhibitors, which are structurally and pharmacologically distinct from cocaine, may be developed as potential cocaine-abuse therapeutics.
为了找到一种治疗可卡因成瘾的药物疗法，人们进行了广泛的研究，旨在阐明这种精神刺激药物强化作用背后的分子机制。这些研究结果与多巴胺转运体（DAT）对多巴胺摄取的抑制作用一致，这会导致突触中外周多巴胺快速过度积累，这是可卡因产生运动刺激作用的主要机制。然而，对5-羟色胺（SERT）和去甲肾上腺素（NET）转运体以及可卡因直接或间接相互作用的其他受体系统的研究表明，DAT并非可卡因强化作用的唯一原因。为了进一步阐明这些系统在可卡因强化作用中的作用，人们设计、合成并表征了以药物分子形式存在的选择性分子探针。这些化合物中的许多都能强效且选择性地与DAT结合，阻断多巴胺再摄取，并且在精神刺激药物滥用的动物模型中表现出类似可卡因的行为。然而，在几类多巴胺摄取抑制剂中发现了例外情况，它们表现出与可卡因不同的行为特征。化学结构多样的多巴胺摄取抑制剂之间的构效关系表明，在DAT分子水平上不同的结合相互作用以及在其他单胺转运体上的不同作用可能与这些化合物在体内不同的药理作用有关。这些研究表明，结构和药理学上与可卡因不同的新型多巴胺摄取抑制剂可能被开发为潜在的可卡因成瘾治疗药物。
