Dopamine Transporter Agents Against Cocaine Dependence

描述（由申请人提供）：迫切需要开发一种药物来治疗可卡因成瘾，这是一种主要的滥用药物。 可卡因的强化作用被认为主要源于其与大脑中的多巴胺转运蛋白（DAT）的结合。然而，可卡因能神经传递的参与也与可卡因的行为效应的表现有关。大量的结构不同的化合物已被开发的DAT可卡因药物的潜在发展。然而，迄今为止，这些努力取得的成功有限。影响到目前为止开发的大多数DAT-阻断剂的另一个缺点是它们对去甲肾上腺素转运蛋白（NET）的固有活性，当测量摄取抑制活性而不是结合效力时，这是显而易见的。在我们的努力，以促进开发药物可卡因成瘾，我们已经合成了一些有效的和选择性的分子的DAT。然而，这些分子中的一些，尽管其有效的体外活性，只有微弱的活性在体内。为了赋予这些分子更好的药效学和药代动力学特性，在上一个资助周期中引入了三个主要的结构修饰。这些变化涉及在我们最初的柔性母体分子中引入刚性，并在中心哌啶环中引入额外的官能团。这些结构改变导致DAT的高效力和更好的选择性，以及与原始柔性母体分子相比高得多的体内活性。从这些SAR研究中开发的一种先导化合物减少了训练用于食物和可卡因的杠杆按压的恒河猴中可卡因的自我给药，表明其在替代疗法中的潜在应用。在该项目的下一阶段，我们建议对这三个系列的药物进行全面的SAR研究，目的是寻找能够有效取代可卡因以实现长期戒断或防止复吸的化合物。我们的建议集中在可卡因的多巴胺能方面的活动。然而，我们还计划合成具有不同程度的5-羟色胺转运体（SERT）活性的化合物，以解决5-羟色胺参与可卡因作用机制的复杂问题。化合物将在单胺转运蛋白摄取和结合测定中表征，以评价其体外活性。将测试基于其体外活性选择的化合物对自发活动和药物辨别的影响，并进行自我给药研究，以评估其在替代治疗中的潜力。

DESCRIPTION (provided by applicant): There is an urgent need for the development of a medication to treat addiction to cocaine, a major drug of abuse. The reinforcing effect of cocaine is believed to originate mainly from its binding to the dopamine transporter (DAT) in the brain. However, involvement of serotonergic neurotransmission has also been implicated in the manifestation of cocaine's behavioral effects. A great number of structurally diverse compounds have been developed for the DAT for potential development of cocaine medications. However, these efforts have met with limited success so far. One other shortcoming which affect most of the DAT-blockers developed so far is their inherent activity for the norepinephrine transporter (NET) which is readily apparent when uptake inhibitory activity is measured rather than binding potency. In our effort to contribute towards developing medications for cocaine addiction, we have synthesized a number of potent and selective molecules for the DAT. However, some of these molecules, in spite of their potent in vitro activity, were only weakly active in vivo. In order to bestow better pharmacodynamic and pharmcokinetic properties to these molecules, three major structural modifications were introduced in the previous funding cycle. These changes involved introduction of rigidity in our original flexible parent molecules and introduction of an additional functionality in the central piperidine ring. These structural alterations resulted in high potency and better selectivity at DAT, and much higher in vivo activity compared to the original flexible parent molecules. One of the lead compounds developed from these SAR studies decreased self-administration of cocaine in rhesus monkey trained to lever press for both food and cocaine, indicating its potential application in substitution therapy. In the next phase of the project, we propose to carry out comprehensive SAR studies in these three series of drugs aiming at compounds that have the ability either to replace cocaine effectively for long-term abstinence or to prevent relapse. Our proposal is focused on the dopaminergic aspect of the activity of cocaine. However, we also plan to synthesize compounds with variable degree of serotonin transporter (SERT) activity to address the complex issue of the involvement of serotonin in the mechanism of action of cocaine. Compounds will be characterized in monoamine transporters uptake and binding assays to evaluate their in vitro activity. Compounds selected based on their in vitro activity will be tested for effects on locomotor activity and drug discrimination and self-administration studies to assess their potential in replacement therapy.