Dopamine Transporter Agents Against Cocaine Dependence

描述（由申请人提供）：目前迫切需要研制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。可卡因的强化作用被认为主要源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影响的表现有关。大量结构多样的化合物已被开发用于DAT，用于潜在的可卡因药物开发。然而，到目前为止，这些努力只取得了有限的成功。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，这种活性很容易显现。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合成了一些有效的选择性分子。然而，尽管其中一些分子在体外具有强大的活性，但在体内的活性却很弱。为了使这些分子具有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种主要的结构修饰。这些变化包括在我们原来的柔性母体分子中引入刚性和在中央哌啶环中引入额外的功能。这些结构改变导致了高效力和更好的选择性在DAT，并比原来的柔性母体分子更高的体内活性。从这些SAR研究中开发的一种先导化合物减少了恒河猴对食物和可卡因的自我给药，表明其在替代疗法中的潜在应用。在项目的下一阶段，我们建议对这三个系列药物进行全面的SAR研究，旨在寻找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血清素转运体（SERT）活性的化合物，以解决血清素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试验中进行表征，以评估其体外活性。根据其体外活性选择的化合物将测试其对运动活动的影响，以及药物识别和自我给药研究，以评估其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.