Novel Pharmacologic Interventions for Drugs of Abuse

描述(申请人提供)：可卡因滥用和中毒在美国和世界上都是对人类健康的严重威胁。到目前为止，还没有有效的治疗方法来治疗与使用可卡因有关的滥用或中毒。针对可卡因作用部位的药物，如多巴胺转运体，取得的成功有限。最近，人们注意到Sigma受体拮抗剂可以减弱和阻断可卡因的毒性和刺激/奖赏效应。因此，Sigma受体是治疗可卡因中毒和成瘾药物开发的有效靶点。Sigma受体以两种不同的亚型存在，Sigma-1和Sigma-2。到目前为止，只有Sigma-1受体被克隆。Sigma-1受体已被证明与可卡因的毒性和成瘾效应有关，并且是开发新疗法的合理靶点。虽然Sigma-2受体的参与还不是很确定，但不能完全排除它们参与的可能性。这一认识受到选择性西格玛-2制剂的影响。然而，现有数据高度暗示他们参与了可卡因的刺激性和毒性作用。因此，我们假设，靶向Sigma-1和Sigma-2受体，无论是联合使用还是通过亚型选择药物，都可以为治疗可卡因中毒和成瘾提供有效的药物。到目前为止，我们已经根据合理的设计(从已知的sigma拮抗剂)合成了30多个结构相关的化合物，这些化合物表现出对sigma-1和sigma-2受体的高亲和力。此外，这些化合物中的一些已经在体内进行了评估，并防止了可卡因引起的惊厥和运动活动。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，对sigma-1、sigma-2具有选择性，或在每个受体上结合亲和力。2)证明这些化合物与最初的例子一样，对Sigma受体具有很高的亲和力，而对其他类型的受体缺乏活性。3)开发基于我们的配体的三维药效团模型，这将有助于确定受体上的配体选择性分布和结合模式，并促进新型配体的父级设计。4)研究新化合物对可卡因诱导行为的抑制作用。

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.