Synthesis and Evaluation of Sigma-Active Cocaine Antagonists

描述（由申请人提供）：可卡因和甲基苯丙胺是当今美国的主要毒品威胁，但没有有效的治疗方法。开发有效的抗可卡因和甲基苯丙胺剂的一种策略是阻止它们获得关键的靶蛋白。在这些精神兴奋剂可以发挥作用的无数位点中，CT受体已经成为药物开发的有希望的靶点。在我们早期资助的项目中，我们证明了选择性α受体拮抗剂可以减弱可卡因和甲基苯丙胺的许多毒性和刺激作用。在两种主要的α受体亚型α 1和α 2中，我们已经能够通过开发亚型选择性配体和通过使用针对受体的序列特异性反义寡核苷酸来证实α 1受体参与许多这些效应。然而，cr2受体的序列仍然是未知的，目前还没有真正的选择性配体结合到a2受体。然而，现有的数据高度提示α 2受体在可卡因和甲基苯丙胺的作用中的作用。因此，我们假设a2受体代表了精神兴奋剂滥用的可行药物开发目标。为了测试这一点，该项目的具体目标是：1）开发具有改进的选择性的新型α 2受体配体，2）确认新型α 2受体配体的亲和力和相对选择性，3）证明选择性α 2受体配体改变可卡因的行为效应，以及4）证明选择性α 2受体配体改变甲基苯丙胺在体内的作用。预期本计画的结果将刺激新a2受体探针的合理开发，并最终有助于改善精神兴奋剂滥用的治疗。

DESCRIPTION (provided by applicant): Cocaine and methamphetamine are leading drug threats in the U.S. today, yet no effective treatments for their abuse are available. One strategy for developing effective anti-cocaine and methamphetamine agents is to block their access to key target proteins. Of the myriad of sites through which these psychomotor stimulants can act, CT receptors have emerged as promising targets for medication development. In our earlier funded project, we demonstrated that selective a receptor antagonists attenuate many of the toxic and stimulant effects of both cocaine and methamphetamine. Of the two major a receptor subtypes, a, and a2, we have been able to confirm the involvement of a-\ receptors in many of these effects through the development of subtype selective ligands and by using sequence specific antisense oligonucleotides against receptors. However, the sequence of cr2 receptors is still unknown and there are currently no truly selective ligands that bind to a2 receptors. The existing data are nonetheless highly suggestive of a role for a2 receptors in the effects of cocaine and methamphetamine. We therefore hypothesize that a2 receptors represent viable medication development targets for psychostimulant abuse. To test this, the specific aims of the project are: 1) To develop novel a2 receptor ligands with improved selectivity, 2) To confirm the affinity and relative selectivity of the novel a2 receptor ligands, 3) To demonstrate that selective a2 receptor ligands alter the behavioral effects of cocaine, and 4) To demonstrate that selective a2 receptor ligands alter the actions of methamphetamine in vivo. It is anticipated that the results of this project will stimulate the rational development of new a2 receptor probes and ultimately contribute to improved treatments for psychostimulant abuse.