GABAB RECEPTOR AGONISTS AND ANTAGONISTS

有证据表明受体介导中枢神经系统对γ- 氨基丁酸（GABA）是异质的， GABA/A和GABA/B之间的差异已被进一步区分 主要受体亚型。 GAVA/a受体被以下物质拮抗： 荷包牡丹碱（BIC），与印防己毒素（PIC）敏感的氯化物连接 通道，至少部分与苯二氮卓类相关 (BZ)识别位点。 相反，GABA/B受体是 对BIC和PIC不敏感，似乎在功能上没有联系 BZ识别位点，并影响电压敏感性钾 和钙电流。 多种激动剂和拮抗剂是 可用于评价GABA/A受体功能。 然而，在这方面， 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。 生化和生理证据表明GABA/A 受体介导的经典突触神经传递 GABA/B受体可能参与了神经元的调节 活动 因此，GABA可能以双重能力起作用， 神经递质和神经调质。 BAC代表广泛使用的解痉剂。 然而，在这方面， 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 开发更有选择性的GABA/B激动剂的可能性 治疗潜力 此外，有理由相信， GABA/B拮抗剂可以具有治疗效用，例如， 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）GABA/B受体激动剂和 拮抗剂代表了一种微妙的方法来影响GABA， 大脑中的媒体事件。 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）体外功能测定 试验和（3）整体动物试验。 将选择化合物 从新星目前的化学品库存中 查明的物剂 因为具有所需的药理学性质将提供铅 在第二阶段启动合成化学工作的结构 申请的一部分。

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.