DEVELOPMENT OF SELECTIVE PCP RECEPTOR LIGANDS

苯环利定(PCP)于1958年作为一种 强效、快速的麻醉剂，不会导致呼吸抑制。 然而，由于精神分裂的一面，它的医学用途是有限的。 效果，并于1965年从医疗用途中撤回。由于PCP是 有时令人愉悦，它成为滥用的主要药物。指导的研究 对五氯苯酚作用机制的了解导致了对 特定的五氯苯酚结合位点。虽然最初的研究表明， PCP的结合部位是单一的实体，进一步的研究表明“PCP 受体“代表多个结合部位。目前至少有 三类重要的PCP受体：1)PCP/NMDA偶联 受体；2)Sigma受体；以及3)PCP-多巴胺再摄取载体。这个 本申请中提出的研究的具体目标是发现 并开发针对PCP/NMDA偶联受体的化合物。按顺序 为了实现这一目标，我们使用了分子建模技术来 鉴定四类具有几何刚性的三环苯基胺 符合我们提出的PCP/NMDA药效团模型。 由于MK801在PCP/NMDA偶联和PCP之间显示出最大的差异。 多巴胺再摄取载体结合部位，我们定制的化合物允许 MK801的结构差异探讨 和五氯苯酚。本研究提供的结构-活性关系信息 将进一步确立PCP受体亚型的概念，并将有助于 为未来设计更具选择性的药物。五氯苯酚配体选择性 只有PCP/NMDA偶联部位可能没有精神活性副作用 并可能对涉及该受体的疾病的治疗有用。

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 However, its medical usefulness was limited due to psychotomimetic side effects, and it was withdrawn from medical use in 1965.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.