DRUG DEVELOPMENT OF SELECTIVE PCP RECEPTOR LIGANDS

苯环己哌啶 (PCP) 是一种拟精神病药物，与 N-相互作用 甲基-D-天冬氨酸 (NMDA) 兴奋性氨基酸受体，胆碱能 受体、钾通道、生物胺转运蛋白 (BAT) 和 西格玛结合位点。与广泛的中枢神经系统一致 系统大分子靶点，PCP具有复杂的药理学作用，包括 人类有很强的滥用倾向。来自多个实验室的多项研究 已经证明，低水平产生的大部分行为效应 动物体内五氯苯酚的剂量是由于非竞争性抑制 NMDA 受体。潜在有用的抗惊厥和神经保护剂 PCP 类化合物的作用也由 NMDA 介导 受体（PCP 位点 1）。最近，可能有用的 报告说明了非竞争性 NMDA 抑制剂在药物成瘾中的作用 NMDA 非竞争性抑制剂 MK801 阻断阿片类药物的能力 耐受和依赖。不幸的是，不良行为 MK801 的影响和神经毒性掩盖了其可能性 好处。 [3H]TCP 已被证明可以标记与以下相关的站点（PCP 站点 2） 生物胺转运蛋白（BAT）。 BAT 配体引起人们的兴趣，因为它们 具有治疗可卡因成瘾各个阶段的潜力。期间 目前，我们发现了三类结构新颖的化合物 选择性结合 PCP 位点 2，其效力比任何 之前报道过的化合物。本次更新的主要具体目标 应用是PCP的设计、合成和生物学评价 位点 2 配体。需要进行此类研究来更全面地描述 位点 2 药效团并了解有关其药理学的更多信息 网站。第二个目标是设计、合成和生物学评价 以(/-)-5-为代表的一类NMDA非竞争性抑制剂 氨基羰基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺 （ADCI）。体外研究表明，此类抑制剂 作为 NMDA 受体通道阻滞剂（非竞争性拮抗剂），结合较弱 但却是低毒的强效抗惊厥药。机制 责任没有明确理解，但将在本节中解决 应用程序。 为了实现上述目标，RTI 结合了其主要业务 专业知识，药物化学和有机合成，拥有三位专家 在生物化学和药理学领域-博士。 NIDA 的理查德·罗斯曼 (ARC) 用于放射性配体结合和放射自显影研究；迈克尔博士 NIH 的 Rogawski 负责抗惊厥和毒性研究；和罗伯特博士 Balster 在 MCV 进行药物歧视研究。为了补充这些 努力，将获得有关目标化合物的更多信息 将它们提交给 CPDD（耐受性和戒断研究）和 可卡因治疗发现计划进行进一步评估。 从这些研究中获得的信息可能会导致开发 用于治疗可卡因成瘾和阿片类药物成瘾的药物 容忍和戒断。

Phencyclidine (PCP) is a psychotomimetic drug that interacts with the N- methyl-D-aspartate (NMDA) excitatory amino acid receptor, cholinergic receptors, potassium channels, biogenic amine transporters (BAT), and sigma binding sites. Consistent with this broad array of central nervous system macromolecular targets, PCP has a complex pharmacology, including a strong abuse liability in humans. Many studies from several laboratories have demonstrated that most of the behavioral effects produced by low doses of PCP in animals result from the uncompetitive inhibition of the NMDA receptor. The potentially useful anticonvulsant and neuroprotective effects of the PCP class of compounds are also mediated by the NMDA receptor (PCP site 1). More recently, the possible usefulness of uncompetitive NMDA inhibitors in drug addiction was illustrated by reports of the ability of the NMDA uncompetitive inhibitor MK801 to block opioid tolerance and dependence. Unfortunately, the undesirable behavioral effects and neurological toxicity of MK801 overshadow its possible benefits. [3H]TCP has been shown to label a site (PCP site 2) associated with the biogenic amine transporter (BAT). BAT ligands are of interest since they have potential in treating various stages of cocaine addiction. During the present grant, we discovered three structurally novel classes of compounds that bind selectively to PCP site 2 with greater potency than any previously reported compounds. The major specific aim of this renewal application is the design, synthesis, and biological evaluation of PCP site 2 ligands. Such studies are needed to more fully characterize the site 2 pharmacophore and to learn more about the pharmacology of this site. A second aim is the design, synthesis, and biological evaluation of a class of NMDA uncompetitive inhibitors represented by (+/-)-5- aminocarbonyl- 10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCI). In vitro studies have demonstrated that this class of inhibitors binds weakly as NMDA receptor-channel-blockers (uncompetitive antagonists) yet are potent anticonvulsants with low toxicity. The mechanism responsible is not clearly understood but will be addressed in this application. In order to accomplish the goals above, RTI has combined its major expertise, medicinal chemistry and organic synthesis, with three experts in the biochemical and pharmacological fields-Dr. Richard Rothman of NIDA (ARC) for radioligand binding and autoradiographic studies; Dr. Michael Rogawski of NIH for anticonvulsant and toxicity studies; and Dr. Robert Balster at MCV for drug discrimination studies. To supplement these efforts, additional information about the target compounds will be gained by submitting them to the CPDD (tolerance and withdrawal studies) and the cocaine treatment discovery program for further evaluation. The information gained from these studies could lead to the development of medications for the treatment of cocaine addiction as well as opiate tolerance and withdrawal.