DOPAMINE TRANSPORTER AGENTS AGAINST COCAINE DEPENDENCE

可卡因是一种强大的强化剂，导致它在过去20年里作为一种主要的滥用药物在美国广泛使用。开发一种药物来治疗这种成瘾是一个迫切的需求。可卡因作用的主要机制归因于它与大脑中多巴胺（DA）转运系统的结合。为了阻断中枢神经系统（CNS）对可卡因的依赖，研究人员开发了许多结构多样的化合物，选择性地与DAT结合，但收效甚微。最近，一种高亲和力的DAT特异性化合物GBR 12909被发现具有较长的作用持续时间，自我给药的效力低于可卡因，并且可以拮抗可卡因的部分作用。在我们的构效关系（SAR）研究中，我们已经开发了新的与GBR 12909相关的强效DAT特异性化合物的哌啶类似物。我们的后续SAR研究导致了该类化合物的第二代开发，其对DAT的选择性远高于传统的GBR分子。在我们最近的一项研究中，用n原子取代苯并水的o原子是这些dat特异性化合物，导致了强效和更极性的新一代n模拟分子的发展。此外，在克隆的人类转运蛋白结合实验中，我们的一些类似物与多巴胺再摄取位点相比，在与可卡因结合位点的结合上表现出显著的选择性。它们的吸收结合比值远远大于任何其他现有化合物的值。在我们最初的小鼠体内运动作用研究中，其中两种类似物在相同剂量下的刺激性低于可卡因和GBR 12909。在与可卡因的联合研究中，这些化合物有效地减弱了可卡因的运动刺激作用。我们现在建议对我们的先导化合物进行SAR研究，以开发具有高多巴胺摄取与结合比的有效和选择性的DAT化合物。将测试选定的化合物对运动作用的影响和药物鉴别研究，以观察它们阻断可卡因作用的能力。我们的目标是开发一种有效的药物来对抗可卡因成瘾。

Cocaine is a strong reinforcer which led to its wide-spread use as a major drug of abuse in U.S.A in the last two decades. The development of a medication to treat this addiction is an urgent requirement. The central mechanism of the action of cocaine is attributed to its binding to the dopamine (DA) transporter system in the brain. Many structurally diverse compounds that bind selectively to the DAT, have been developed with an aim to block cocaine dependence in the central nervous system (CNS), but they met with only limited success. Recently, a high affinity DAT- specific compound GBR 12909 was found to have longer duration of action, was self-administered less potently than cocaine, and could antagonize some of the cocaine action. In our structure- activity relationship (SAR) study, we have shown the development of novel piperidine analogs of GBR 12909-related potent DAT- specific compounds. Our follow-up SAR study led to the development of a second generation of compounds in this class with far more selectivity for the DAT than conventional GBR molecules. In one of our recent studies, replacement of the benzhydrylic O-atom by an N-atom is these DAT-specific compounds, led to the development of potent and more polar, new-generation N-analog molecules. Furthermore, some of our analogs showed remarkable selectivity for binding to the cocaine binding site compared to the dopamine reuptake site in the cloned human transporters binding assay. The values of their uptake to binding ratio were far greater than values of any other existing compounds. In our initial in-vivo motor action studies in mice, two of these analogs were less stimulatnt than cocaine and GBR 12909 at similar doses. In combination studies with cocaine, these compounds attenuated the locomotor stimulatory effect of cocaine efficiently. We now propose to follow up on the SAR studies of our lead compounds to develop potent and selective compounds for the DAT with high dopamine uptake to binding ratio. Selected compounds will be tested for their effects on locomotor action and drug discrimination studies to observe their ability to block cocaine action. Our goal is to develop an effective medication against cocaine addiction.