DEVELOPMENT OF SELECTIVE PCP RECEPTOR LIGANDS

苯环利定（PCP）于1958年作为一种 一种不引起呼吸抑制的强效速效麻醉剂。 然而，由于其具有拟精神病的一面，其医疗用途受到限制 1965年，它被从医疗用途中撤出。 由于PCP是 有时会令人兴奋，它成为一种主要的滥用药物。 指导的研究 为了了解PCP的作用机制， 特定的五氯苯酚结合位点。 虽然最初的研究表明， 五氯苯酚结合位点是一个单一的实体，进一步的研究表明，“五氯苯酚 “受体”代表多个结合位点。 目前，至少有 三种重要的“五氯苯酚受体”：1）五氯苯酚/NMDA偶联 受体; 2）σ受体;和3）PCP-多巴胺再摄取载体。 的 本申请中提出的研究的具体目的是发现 并开发针对PCP/NMDA偶联受体的特异性化合物。 为了 为了实现这一目标，我们使用了分子模拟技术， 确定了四类几何刚性的三环苄基胺， 符合我们提出的PCP/NMDA药效团模型。 由于MK 801在PCP/NMDA偶联和PCP-NMDA偶联之间显示出最大的差异， 多巴胺再摄取载体结合位点，我们定制了化合物， MK 801结构差异的探索 和PCP。 本研究得到的构效关系信息 进一步建立PCP受体亚型概念， 用于未来设计更多选择性药物。 五氯苯酚配体对 只有PCP/NMDA偶联位点可能没有精神活性副作用 并且可能用于治疗涉及该受体的疾病。

Phencyclidine (PCP) was introduced into clinical practice in 1958 as a potent, fast-acting anesthetic that did not cause respiratory depression. However, its medical usefulness was limited due to psychotomimetic side effects, and it was withdrawn from medical use in 1965. Since PCP is sometimes euphorigenic, it became a major drug of abuse. Studies directed toward understanding PCP's mechanism of action led to the identification of specific PCP binding sites. While the original studies suggested that the PCP binding site was a single entity, further studies have shown "PCP receptors" represent multiple binding sites. At present there are at least three significant classes of "PCP receptors": 1) PCP/NMDA-coupled receptors; 2) sigma receptors; and 3) PCP-dopamine reuptake carriers. The specific aim of the research proposed in this application is to discover and develop compounds specific for the PCP/NMDA-coupled receptor. In order to achieve this goal, we have used molecular modeling techniques to identify four classes of geometrically rigid tricyclic benzylic amines that fit the PCP/NMDA pharmacophore model that we have proposed. Since MK801 shows the greatest difference between PCP/NMDA-coupled and PCP- dopamine reuptake carrier binding site, we tailored the compounds to allow exploration of the structural differences between the structures of MK801 and PCP. The structure-activity relationship information from this study will establish further the PCP receptor subtype concept and will be helpful for the future design of more selective drugs. PCP ligands selective for only the PCP/NMDA-coupled site might be free of psychoactive side effects and might be useful for the treatment of disorders involving this receptor.