SGS742:: the first GABAB receptor antagonist in clinical trials
SGS742:: the first GABAB receptor antagonist in clinical trials
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DOI：
10.1016/j.bcp.2004.07.030
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发表时间：
2004-10-15
影响因子：
5.8
通讯作者：
Pearlman, R
中科院分区：
文献类型：
--
作者：
Froestl, W;Gallagher, M;Pearlman, R
GABA(B)受体拮抗剂SGS742(CGP36742)在小鼠、幼年和老年大鼠以及猕猴的主动和被动回避范式、八臂径向迷宫和Morris水迷宫以及社会学习任务中显示出显著的认知增强作用。SGS742阻断大鼠在体内外CA1区锥体神经元记录到的突触后迟发性抑制电位和群峰电位的双脉冲抑制。SGS742可显著促进谷氨酸、天冬氨酸、甘氨酸和生长抑素的体内释放。长期给予SGS742可引起大鼠额叶皮质GABA(B)受体表达上调。单次给药组大鼠大脑皮层和海马区NGF和BDNF的mRNA和蛋白水平均显著升高。SGS742在大鼠身上观察到的抗抑郁作用可以用这些发现来解释。SGS742在实验动物以及年轻和老年志愿者中都有很好的耐受性，在人类中的绝对生物利用度为44%。在一项对110名轻度认知障碍(MCI)患者进行的II期双盲安慰剂对照研究中，口服SGS742 600 mg，tid。在8周内，注意力显著改善，特别是选择反应时和视觉信息处理，以及以模式识别速度衡量的工作记忆。在280名阿尔茨海默病患者中进行的第二阶段临床试验正在进行中。(C)2004 Elsevier Inc.保留所有权利。
The GABA(B) receptor antagonist SGS742 (CGP36742) displays pronounced cognition enhancing effects in mice, young and old rats and in Rhesus monkeys in active and passive avoidance paradigms, in an eight-arm radial maze and a Morris water maze and in a social learning task. SGS742 blocks the late inhibitory postsynaptic potential and the paired-pulse inhibition of population spikes recorded from CA1 pyramidal neurons of the hippocampus of rats in vitro and in vivo. SGS742 significantly enhances the release of glutamate, aspartate, glycine and somatostatin in vivo. Chronic administration of SGS742 causes an up-regulation of GABA(B) receptors in the frontal cortex of rats. Single doses cause a significant enhancement of the mRNA and protein levels of NGF and BDNF in the cortex and hippocampus of rats. The observed antidepressant effects of SGS742 in rats may be explained by these findings.SGS742 was well tolerated in experimental animals as well as in young and elderly human volunteers with an absolute bioavailability in humans of 44%.In a Phase II double-blind, placebo-controlled study in 110 patients with mild cognitive impairment (MCI), oral administration of SGS742 at a dose of 600 mg t.i.d. for 8 weeks significantly improved attention, in particular choice reaction time and visual information processing as well as working memory measured as pattern recognition speed. A second Phase II clinical trial in 280 Alzheimer's disease patients is underway. (C) 2004 Elsevier Inc. All rights reserved.