DOPAMINE TRANSPORTER AGENTS AGAINST COCAINE DEPENDENCE

可卡因是一种强有力的增强剂，在过去的二十年里，它作为一种主要的滥用药物在美国得到了广泛的使用。开发一种治疗这种成瘾的药物是当务之急。可卡因作用的中心机制归因于它与大脑中的多巴胺(DA)转运系统的结合。许多结构多样的化合物选择性地与DAT结合，目的是为了阻止中枢神经系统(CNS)对可卡因的依赖，但它们只取得了有限的成功。最近，一种高亲和力的DAT特异性化合物GBR 12909被发现具有更长的作用时间，自我给药的效力低于可卡因，并可以拮抗一些可卡因的作用。在我们的构效关系研究中，我们展示了与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研究导致了这一类第二代化合物的开发，与传统的GBR分子相比，DAT的选择性要高得多。在我们最近的一项研究中，苯基O-原子被N-原子取代是这些DAT特有的化合物，导致了强大的、更具极性的新一代N-类似物的发展。此外，在克隆的人转运蛋白结合实验中，我们的一些类似物显示出与可卡因结合部位的结合比与多巴胺再摄取部位的结合具有显著的选择性。它们的摄取与结合比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动作研究中，其中两个类似物的刺激性低于类似剂量的可卡因和12909英镑。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。我们现在建议跟进我们的先导化合物的SAR研究，以开发有效和选择性的化合物，用于DAT，具有高多巴胺摄取与结合比率。选定的化合物将被测试它们对运动行为的影响，并进行药物识别研究，以观察它们阻止可卡因行为的能力。我们的目标是开发一种有效的治疗可卡因成瘾的药物。

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.