GABAB RECEPTOR AGONISTS AND ANTAGONISTS

GABAB 受体激动剂和拮抗剂

• 批准号: 3504188
• 负责人: JOHN W FERKANY
• 金额: $ 4.92万
• 依托单位: NOVA PHARMACEUTICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 1988-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3504188
• 关键词: GABA receptor; analgesics; bioassay; chemical binding; cyclic AMP; dosage; drug screening /evaluation; gamma aminobutyrate; isoproterenol; laboratory mouse; laboratory rat; ligands; neuropharmacologic agent; neuropharmacology; neurotransmitters; radiotracer; scintillation spectrometry; tritium

Evidence suggests receptors mediating CNS responses to gamma- aminobutyric acid (GABA) are heterogeneous and the designations of GABA/A and GABA/B have been advanced to differentiate major receptor subtypes. GAVA/a receptors are antagonized by bicuculline (BIC), linked to a picrotoxin (PIC)-sensitive chloride channel and, at least partially, associated with benzodiazepine (BZ) recognition sites. In contrast, GABA/B receptors are insensitive to BIC and PIC, do not appear to be functionally linked to BZ recognition sites and influence voltage-sensitive potassium and calcium currents. Multiple agonists and antagonist are available to evalutae GABA/A receptors function. However, baclofen (BAC) is the only selective agonist for GABA receptors and no potent and specific antagonists have been identified. Biochemical and physiological evidence indicate GABA/A receptor mediate classical synaptic neurotransmission wheras GABA/B receptors may be involved in modulation of neuronal activity. Thus, GABA may function in a dual capacity as a neurontransmitter and neuromodulator in brain. BAC represents a widely used antispastic agent. However, deleterious side-effects attending BAC administration are documented. Heterogenety among GABA/B receptors suggests the possibility of developing more selective GABA/B agonists of therapeutic potential. Furthermore, reason exists to beleive that GABA/B antagonists could be of therapeutic utility, for instance, in the reatment of Parkinson Disease or as CNS stimulants. Because such compounds would modulate rather than mimick (inhibit) neutrotransmission, GABA/B receptor agonists and antagonists would represent a subtle approach to influence GABA- mediaed events in brain. The Phase I proposal seeks support to develop a program to identify GABA/B receptor agonists and antagonist. Methods will include (1) in vitro ligand binding assays, (2) in vitro functional assays and (3) whole animal testing. Compounds will be selected from Nova's current inventory of chemicals. Agents indentified as having the desired pharmacological properties will provide lead structures to initiate synthetic chemical efforts in the Phase II portion of the application.

有证据表明受体介导中枢神经系统对γ-的反应 氨基丁酸 (GABA) 是异质的，名称 GABA/A 和 GABA/B 已被改进以区分 主要受体亚型。 GAVA/a 受体被拮抗 荷包牡丹碱 (BIC)，与印防己毒素 (PIC) 敏感的氯化物有关 通道，并且至少部分与苯二氮卓类相关 (BZ) 识别位点。 相比之下，GABA/B 受体是 对 BIC 和 PIC 不敏感，似乎没有功能关联 BZ 识别位点并影响电压敏感钾 和钙流。 多种激动剂和拮抗剂 可用于评估 GABA/A 受体功能。 然而， 巴氯芬 (BAC) 是 GABA 受体的唯一选择性激动剂 并且尚未鉴定出有效且特异性的拮抗剂。 生化和生理学证据表明 GABA/A 受体介导经典突触神经传递 GABA/B 受体可能参与神经元的调节 活动。 因此，GABA 可能具有双重功能： 大脑中的神经递质和神经调节剂。 BAC 是一种广泛使用的镇痉剂。 然而， BAC 给药的有害副作用是 记录在案。 GABA/B 受体之间的异质性表明 开发更具选择性的 GABA/B 激动剂的可能性 治疗潜力。 此外，有理由相信 GABA/B 拮抗剂可能具有治疗作用，例如， 用于治疗帕金森病或作为中枢神经系统兴奋剂。 因为这些化合物会调节而不是模仿 （抑制）中性传递、GABA/B 受体激动剂和 拮抗剂将代表一种影响 GABA 的微妙方法 大脑中的中介事件。 第一阶段提案寻求支持以制定一项计划 鉴定 GABA/B 受体激动剂和拮抗剂。 方法将 包括（1）体外配体结合测定，（2）体外功能 化验和（3）整体动物测试。 将选择化合物 来自 Nova 目前的化学品库存。 代理已确定 因为具有所需的药理特性将提供铅 启动第二阶段合成化学工作的结构 申请的一部分。