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，可卡因是一种主要的滥用药物。可卡因的增强作用被认为主要来自于它与大脑中的多巴胺转运体(DAT)的结合。然而，5-羟色胺能神经传递的参与也与可卡因的行为效应的表现有关。为了开发潜在的可卡因药物，已经为DAT开发了大量结构多样的化合物。然而，到目前为止，这些努力取得的成果有限。到目前为止，影响大多数DAT阻滞剂的另一个缺点是它们对去甲肾上腺素转运体(NET)的固有活性，当测量摄取抑制活性而不是结合效力时，这一点很明显。在我们努力为开发治疗可卡因成瘾的药物做出贡献的过程中，我们已经为DAT合成了一些有效和选择性的分子。然而，这些分子中的一些，尽管它们在体外具有强大的活性，但在体内只具有微弱的活性。为了赋予这些分子更好的药效学和药代动力学特性，在上一个资金周期中引入了三个主要的结构修改。这些变化包括在我们最初的柔性母体分子中引入刚性，以及在中心哌烷环中引入额外的官能团。这些结构变化导致DAT的高效性和更好的选择性，与最初的柔性母体分子相比，在体内的活性要高得多。从这些合成孔径雷达研究中开发出的一种先导化合物减少了恒河猴对可卡因的自我给药，表明它在替代疗法中的潜在应用。在该计划的下一阶段，我们建议对这三个系列药物进行全面的SAR研究，以期找到能够有效替代可卡因长期戒断或防止复发的化合物。我们的建议集中在可卡因活动的多巴胺能方面。然而，我们也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。化合物将通过单胺转运体摄取和结合试验来表征，以评估它们的体外活性。根据它们的体外活性选择的化合物将被测试对运动活性和药物识别的影响，并进行自我给药研究，以评估它们在替代疗法中的潜力。

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.