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主要的毒品威胁，但对其滥用没有有效的治疗方法。开发有效的抗可卡因和甲基苯丙胺药物的一个策略是阻止它们接近关键的靶蛋白。在这些精神运动兴奋剂可以作用的无数位点中，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a受体拮抗剂减弱了可卡因和甲基苯丙胺的许多毒性和刺激性作用。在两种主要的a受体亚型a和a2中，我们已经能够通过亚型选择性配体的发展和对受体使用序列特异性反义寡核苷酸来证实a受体参与了许多这些作用。然而，cr2受体的序列仍然是未知的，目前还没有真正选择性的配体结合a2受体。尽管如此，现有的数据仍然高度暗示了a2受体在可卡因和甲基苯丙胺作用中的作用。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。为了验证这一点，该项目的具体目标是：1)开发具有更高选择性的新型a2受体配体，2)确认新型a2受体配体的亲和力和相对选择性，3)证明选择性a2受体配体改变可卡因的行为效应，4)证明选择性a2受体配体改变甲基苯丙胺在体内的作用。预计该项目的结果将刺激新的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方法。

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.