DRUG DEVELOPMENT OF SELECTIVE PCP RECEPTOR LIGANDS

苯环利定(PCP)是一种类似精神分裂症的药物，它与N-氨基丁酸相互作用。 甲基-D-天冬氨酸兴奋性氨基酸受体胆碱能 受体、钾通道、生物胺转运体(BAT)和 西格玛结合位点。与这种广泛的中枢神经排列相一致 系统的大分子靶点，五氯苯酚具有复杂的药理作用，包括 在人类身上有很强的虐待倾向。来自几个实验室的许多研究 已经证明了低血压产生的大部分行为影响 动物体内五氯苯酚的剂量是由于对 NMDA受体。潜在有用的抗惊厥和神经保护药物 PCP类化合物的作用也是由NMDA介导的 受体(PCP位点1)。最近，可能的用处是 非竞争性NMDA抑制剂在药物成瘾中的应用 NMDA非竞争性抑制剂MK801阻断阿片类药物的能力 宽容和依赖。不幸的是，不良行为 MK801的疗效和神经毒性盖过了其可能的作用 福利。 [3H]已经证明，TCP可以标记与以下内容相关联的站点(PCP站点2 生物胺转运蛋白(BAT)蝙蝠配体很有兴趣，因为它们 在治疗不同阶段的可卡因成瘾方面具有潜力。在.期间 目前，我们发现了三类结构新颖的化合物 选择性地与PCP位点2结合的能力比任何 以前报道过的化合物。这次更新的主要具体目标是 应用于五氯酚的设计、合成和生物评价 第2位配基。需要这样的研究来更全面地描述 站点2的药效团，并了解更多关于这个的药理学 地点。第二个目标是设计、合成和生物评价 一类以(/-)-5-为代表的NMDA非竞争性抑制剂 氨基甲酰基-10，11-二氢-5H-二苯并[a，d]环庚烯-5，10-亚胺 (ADCI)。体外研究表明，这类抑制剂 作为NMDA受体-通道阻滞剂(非竞争性拮抗剂)结合较弱 然而，它们都是低毒的强效抗惊厥药物。这一机制 责任没有被清楚地理解，但将在下面的 申请。 为了实现上述目标，RTI将其主要业务 专业知识、药物化学和有机合成，有三名专家 在生化和药理学领域--Dr。NIDA的理查德·罗斯曼 (ARC)用于放射性配基结合和放射自显影研究；迈克尔博士 美国国立卫生研究院的罗加夫斯基用于抗惊厥药物和毒性研究；罗伯特博士 巴尔斯特在MCV进行药物歧视研究。来补充这些 努力，将获得有关目标化合物的更多信息 通过将其提交给CPDD(容忍和戒断研究)和 可卡因治疗发现方案有待进一步评估。 从这些研究中获得的信息可能会导致 治疗可卡因成瘾的药物和鸦片类药物 宽容和退缩。

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.