Lasztóczi Bálint, Emri Zsuzsa, Szárics Eva, Héja László, Simon Agnes, Nyikos Lajos, Kardos Julianna
Department of Neurochemistry, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, 1025 Pusztaszeri út 59-67, Budapest, Hungary.
Neurochem Int. 2006 Jul;49(1):41-54. doi: 10.1016/j.neuint.2005.12.017. Epub 2006 Feb 21.
We present data on the antiepileptic potency of 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine (Q5) in juvenile (P9-13) rat hippocampal slices and in particular Q5's action mechanism and target. Q5 (200-500 microM), but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/Kainate receptor antagonists blocked low-[Mg2+]-induced seizure-like events (SLE) in the CA3 region. Q5 (100 microM) decreased Glu-induced [35S]guanosine 5'-O-(3-thiotriphosphate) binding enhancement in brain homogenates, without interaction with ionotropic Glu receptor sites and Glu transport. In voltage-clamped CA3 pyramidal cells, Q5 (500 microM) depressed activities of spontaneous excitatory and inhibitory postsynaptic currents without affecting miniature inhibitory currents. Metabotropic Glu receptor (mGluR) subtype antagonists affected network excitability dissimilarly. Intracellular Ca2+ ion transients induced by the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) were suppressed by Q5. Agreeing predictions obtained by modelling Q5 binding to different experimental conformations of mGlu1, Q5 was bound partially to an mGluR binding site in the presence of 1mM ACPD. Findings suggest the apparent involvement of a novel phenotype of action or a new mGluR subtype in the specific suppression of epileptiform activity by Q5 through the depression of network excitability.
我们展示了2-甲基-4-氧代-3H-喹唑啉-3-乙酰哌啶（Q5）在幼年（P9 - 13）大鼠海马切片中的抗癫痫效力数据，特别是Q5的作用机制和靶点。Q5（200 - 500微摩尔），但α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）/海人酸受体拮抗剂不能阻断低[Mg2 +]诱导的CA3区癫痫样事件（SLE）。Q5（100微摩尔）可降低脑匀浆中谷氨酸（Glu）诱导的[35S]鸟苷5'-O-（3-硫代三磷酸）结合增强，且不与离子型Glu受体位点和Glu转运相互作用。在电压钳制的CA3锥体细胞中，Q5（500微摩尔）可抑制自发性兴奋性和抑制性突触后电流的活动，而不影响微小抑制电流。代谢型Glu受体（mGluR）亚型拮抗剂对网络兴奋性的影响不同。Q5可抑制mGluR激动剂（1S，3R）-1-氨基环戊烷-1,3-二羧酸（ACPD）诱导的细胞内Ca2 +离子瞬变。与通过模拟Q5与mGlu1不同实验构象结合获得的预测结果一致，在1毫摩尔ACPD存在下，Q5部分结合到mGluR结合位点。研究结果表明，Q5通过抑制网络兴奋性对癫痫样活动的特异性抑制中，明显涉及一种新的作用表型或一种新的mGluR亚型。
