Novel Pharmacologic Interventions for Drugs of Abuse

描述（由申请人提供）：在美国和世界范围内，可卡因滥用和毒性严重威胁人类健康。到目前为止，还没有有效的治疗方法来治疗与可卡因使用有关的滥用或毒性。靶向可卡因作用位点的药物，如多巴胺转运蛋白，取得了有限的成功。最近，已经注意到σ受体拮抗剂可以减弱和阻断可卡因的毒性和刺激/奖励作用。因此，σ受体是用于治疗可卡因毒性和成瘾的药物开发的有效靶标。σ受体存在两种不同的亚型，σ-1和σ-2。迄今为止，只有sigma-1受体被克隆。σ-1受体已被证明参与可卡因的毒性和成瘾作用，并且是开发新疗法的逻辑靶点。虽然sigma-2受体的参与还没有得到很好的证实，但不能完全排除它们的参与。这方面的知识受到了选择性sigma-2代理商可用性的阻碍。然而，现有数据高度表明，它们参与可卡因的兴奋剂和毒性作用。因此，我们假设靶向sigma-1和sigma-2受体，无论是组合还是通过亚型选择性药物，都可以提供治疗可卡因毒性和成瘾的有效药物。迄今为止，我们已经产生了超过三十个，结构相关的化合物的基础上合理的设计（从已知的σ拮抗剂），已证明高亲和力的σ-1和σ-2受体。此外，这些化合物中的一些已经在体内进行了评估，并防止可卡因诱导的惊厥和自发活动。为了验证我们的假设，该项目的具体目标是：1）以平行合成的方式开发新的sigma-1和sigma-2配体，这些配体对sigma-1，sigma-2具有选择性，或者对每个受体具有亲和力的组合。2)为了证明这些化合物如初步实施例对σ受体具有高亲和力，而对其他受体类型缺乏活性。3)开发三维药效团模型，基于我们的配体，这将有助于定义配体的选择性概况和在受体上的结合模式，并促进新配体的父设计。4)证明新化合物减弱可卡因诱导的行为。

DESCRIPTION (provided by applicant): Cocaine abuse and toxicities are serious threats to human health in the United States and the World. To date, there are no effective treatments for the abuse or toxicities associated with cocaine use. Agents targeting the sites of action of cocaine, such as the dopamine transporter, have met with limited success. Recently, it has been noted that sigma receptor antagonists can attenuate and block the toxic and the stimulant/rewarding effects of cocaine. Thus, the sigma receptor is a valid target for medication development for the treatment of cocaine toxicities and addiction. Sigma receptors exist as two distinct subtypes, sigma-1 and sigma-2. To date, only the sigma-1 receptor has been cloned. Sigma-1 receptors have been shown to be involved in the toxic and addictive effects of cocaine and are a logical target for the development of novel therapeutics. Although the involvement of sigma-2 receptors is not well-established, their involvement cannot be completely ruled out. This knowledge has been hampered by the availability of selective sigma-2 agents. However, existing data is highly suggestive of their involvement in the stimulant and toxic effects of cocaine. We therefore hypothesize that targeting sigma-1 and sigma-2 receptors, either in combination or through subtype-selective agents, can provide effective medications for treatment of cocaine toxicities and addiction. To date we have generated over thirty, structurally-related compounds based on a rational design (from known sigma antagonists) that have demonstrated high affinity for sigma-1 and sigma-2 receptors. In addition, some of these compounds have been evaluated in vivo and prevented cocaine-induced convulsions and locomotor activity. To test our hypothesis, the specific aims of the project are: 1) To develop, in a parallel synthesis fashion, novel sigma-1 and sigma-2 ligands with either selectivity for sigma-1, sigma-2, or a combination of affinities at each receptor. 2) To demonstrate these compounds like the preliminary examples have high affinity for sigma receptors and lack activity for other receptor types. 3) To develop three-dimensional pharmacophore models, based on our ligands that will help define the ligands selectivity profile and mode of binding at the receptor and promote father design of novel ligands. 4) To demonstrate the novel compounds attenuate cocaine-induced behaviors.