GABAB RECEPTOR AGONISTS AND ANTAGONISTS

有证据表明，受体介导中枢神经系统对伽马射线的反应。 氨基丁酸(GABA)是多相的，其名称 提出了区分GABA/A和GABA/B的新方法 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)敏感的氯化物相连 通道，并至少部分与苯二氮类药物有关 (Bz)认可网站。相比之下，GABA/B受体 对BIC和PIC不敏感，似乎在功能上没有关联 对BZ识别位点的影响及对压敏钾的影响 和钙电流。多种激动剂和拮抗剂 可用于评估GABA/A受体的功能。然而， 巴氯芬(BAC)是唯一的GABA受体选择性激动剂 目前还没有发现任何有效和特定的拮抗剂。 生化和生理证据表明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可以在双重能力下作为一种 大脑中的神经递质和神经调质。 BAC是一种广泛使用的解痉剂。然而， BAC管理的有害副作用是 有记录在案。GABA/B受体的异质性提示 开发更具选择性的GABA/B受体激动剂的可能性 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。 因为这样的化合物会调节而不是模仿 (抑制)中性粒细胞传递、GABA/B受体激动剂和 拮抗剂将代表一种微妙的方法来影响GABA- 大脑中的媒介事件。 第一阶段提案寻求支持，以制定一项计划，以 确定GABA/B受体激动剂和拮抗剂。方法将 包括(1)体外配基结合分析，(2)体外功能 (3)全动物试验。化合物将被选中 从Nova目前的化学品库存中。已识别的代理 因为具有所需的药理特性将提供铅 在第二阶段启动合成化学工作的结构 应用程序的一部分。

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.