DOPAMINE TRANSPORTER AGENTS AGAINST COCAINE DEPENDENCE

可卡因是一种强效麻醉剂，在过去的20年里，可卡因在美国被广泛使用，成为一种主要的滥用药物。 开发一种治疗这种成瘾的药物是一项迫切的要求。 可卡因作用的中心机制是与大脑中的多巴胺（DA）转运系统结合。 已经开发了许多选择性结合DAT的结构多样的化合物，目的是阻断中枢神经系统（CNS）中的可卡因依赖性，但它们只取得了有限的成功。 最近，发现高亲和力DAT特异性化合物GBR 12909具有更长的作用持续时间，自我施用的效力低于可卡因，并且可以拮抗一些可卡因作用。 在我们的结构-活性关系（SAR）研究中，我们已经展示了GBR 12909相关的强效DAT特异性化合物的新型哌啶类似物的开发。 我们的后续SAR研究导致了第二代化合物的开发，这类化合物对DAT的选择性远远高于传统的GBR分子。 在我们最近的一项研究中，用N-原子取代二苯甲基O-原子是这些DAT特异性化合物，导致了有效和更极性的新一代N-类似物分子的发展。 此外，我们的一些类似物显示出显着的选择性结合到可卡因结合位点相比，多巴胺再摄取位点在克隆人转运蛋白结合试验。 它们的摄取与结合比率的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，这些类似物中的两种在相似剂量下比可卡因和GBR 12909刺激性小。 在与可卡因的组合研究中，这些化合物有效地减弱可卡因的运动刺激作用。 我们现在建议跟进我们的先导化合物的SAR研究，以开发具有高多巴胺摄取结合比的DAT的有效和选择性化合物。将测试所选化合物对运动作用的影响，并进行药物辨别研究，以观察其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.