DRUG DEVELOPMENT OF SELECTIVE PCP RECEPTOR LIGANDS

选择性五氯苯酚受体配体的药物开发

• 批准号: 2331142
• 负责人: FRANK Ivy CARROLL
• 金额: $ 16.75万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2331142
• 关键词: NMDA receptors; PCP receptor; anticonvulsants; dopamine transporter; drug design /synthesis /production; drug tolerance; drug withdrawal; protein structure function; psychopharmacology; receptor binding; receptor sensitivity

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.

苯环利定（PCP）是一种拟精神病药物，与N- 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 σ结合位点。与这些广泛的中枢神经系统一致 系统大分子靶点，PCP具有复杂的药理作用，包括 在人类中有很强的虐待倾向。来自多个实验室的多项研究 已经证明，大多数的行为影响所产生的低 五氯苯酚在动物体内的剂量是由于 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， 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MK 801阻断阿片类药物的能力 宽容和依赖。不幸的是，这种不良行为 MK 801的作用和神经毒性掩盖了其可能的 效益 [3 H]TCP已被证明可以标记与 生物胺转运蛋白（BAT）。BAT配体是令人感兴趣的，因为它们 在治疗可卡因成瘾的各个阶段都有潜力。期间 目前，我们发现了三种结构新颖的化合物 选择性地与PCP位点2结合， 此前报道的化合物。这次更新的主要具体目标是 应用是五氯苯酚的设计、合成和生物学评价 位点2配体。需要进行此类研究，以更全面地描述 网站2药效团，并了解更多关于这一药理学 绝佳的价钱第二个目标是设计、合成和生物学评价 一类NMDA非竞争性抑制剂，由（+/-）-5- 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，这类抑制剂 作为NMDA受体通道阻滞剂（非竞争性拮抗剂）弱结合 而且是低毒性的有效抗惊厥药。机制 责任并不清楚，但将在此解决 应用程序. 为了实现上述目标，RTI结合了其主要的 药物化学和有机合成方面的专业知识，有三名专家 在生物化学和药理学领域-NIDA的理查德·罗斯曼博士 (ARC)用于放射性配体结合和放射自显影研究; Michael博士 抗惊厥药和毒性研究的Rogawski博士; MCV的Balster进行药物歧视研究。为补充这些 通过努力，将获得关于目标化合物的更多信息 通过将其提交给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 治疗可卡因成瘾的药物以及鸦片制剂 宽容和退缩。

项目成果

RTI-4793-14, a new ligand with high affinity and selectivity for the (+)-MK801-insensitive [3H]1-]1-(2-thienyl)cyclohexyl]piperidine binding site (PCP site 2) of guinea pig brain.

RTI-4793-14，一种新配体，对豚鼠脑的 ( )-MK801 不敏感 [3H]1-]1-(2-噻吩基)环己基]哌啶结合位点（PCP 位点 2）具有高亲和力和选择性。

• DOI: 10.1002/syn.890160107
• 发表时间: 1994
• 期刊: Synapse (New York, N.Y.)
• 作者: Goodman,CB;Thomas,DN;Pert,A;Emilien,B;Cadet,JL;Carroll,FI;Blough,BE;Mascarella,SW;Rogawski,MA;Subramaniam,S
• 通讯作者: Subramaniam,S