Novel Pharmacologic Interventions for Drugs of Abuse

说明（由申请人提供）：可卡因的滥用和毒性是对美国和世界人类健康的严重威胁。迄今为止，对可卡因的滥用或与可卡因使用有关的毒性没有有效的治疗方法。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兴奋/奖励作用。因此，sigma受体是治疗可卡因毒性和成瘾的药物开发的有效靶点。Sigma受体有两种不同的亚型，Sigma -1和Sigma -2。迄今为止，只有sigma-1受体被克隆出来。Sigma-1受体已被证明与可卡因的毒性和成瘾性作用有关，是开发新型治疗方法的一个合乎逻辑的目标。虽然还没有确定sigma-2受体的参与，但不能完全排除它们的参与。这种认识一直受到选择性sigma-2试剂可用性的阻碍。然而，现有的数据高度暗示它们参与了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，无论是联合使用还是通过亚型选择性药物，都可以为治疗可卡因毒性和成瘾提供有效的药物。迄今为止，我们已经基于合理的设计（从已知的sigma拮抗剂）生成了超过30种结构相关的化合物，这些化合物对sigma-1和sigma-2受体具有高亲和力。此外，这些化合物中的一些已经在体内进行了评估，并预防可卡因引起的抽搐和运动活动。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，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)证明这些化合物与初步的例子一样，对sigma受体具有高亲和力，而对其他类型的受体缺乏活性。3)基于我们的配体建立三维药效团模型，这将有助于确定配体在受体上的选择性谱和结合模式，并促进新配体的设计。4)证明新化合物能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.