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AMPA受体新型正变构调节剂S 47445的药理学特性

Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors.

作者信息

Bretin Sylvie, Louis Caroline, Seguin Laure, Wagner Stéphanie, Thomas Jean-Yves, Challal Sylvie, Rogez Nathalie, Albinet Karine, Iop Fabrice, Villain Nadège, Bertrand Sonia, Krazem Ali, Bérachochéa Daniel, Billiald Stéphanie, Tordjman Charles, Cordi Alex, Bertrand Daniel, Lestage Pierre, Danober Laurence

机构信息

Pôle Innovation Thérapeutique Neuropsychiatrie, Institut de Recherches Internationales Servier, Suresnes, France.

Pôle Innovation Thérapeutique Neuropsychiatrie, Institut de Recherches Servier, Croissy sur Seine, France.

出版信息

PLoS One. 2017 Sep 8;12(9):e0184429. doi: 10.1371/journal.pone.0184429. eCollection 2017.

Abstract

S 47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPA-PAM). S 47445 enhanced glutamate's action at AMPA receptors on human and rat receptors and was inactive at NMDA and kainate receptors. Potentiation did not differ among the different AMPA receptors subtypes (GluA1/2/4 flip and flop variants) (EC50 between 2.5-5.4 μM), except a higher EC50 value for GluA4 flop (0.7 μM) and a greater amount of potentiation on GluA1 flop. A low concentration of S 47445 (0.1 μM) decreased receptor response decay time of GluA1flop/GluA2flip AMPA receptors and increased the sensitivity to glutamate. Furthermore, S 47445 (0.1 and 0.3 μM) in presence of repetitive glutamate pulses induced a progressive potentiation of the glutamate-evoked currents from the second pulse of glutamate confirming a rapid-enhancing effect of S 47445 at low concentrations. The potentiating effect of S 47445 (1 μM) was concentration-dependently reversed by the selective AMPA receptor antagonist GYKI52466 demonstrating the selective modulatory effect of S 47445 on AMPA receptors. Using an AMPA-kainate chimera approach, it was confirmed that S 47445 binds to the common binding pocket of AMPA-PAMs. S 47445 did not demonstrate neurotoxic effect against glutamate-mediated excitotoxicity in vitro, in contrast significantly protected rat cortical neurons at 10 μM. S 47445 was shown to improve both episodic and spatial working memory in adult rodents at 0.3 mg/kg, as measured in the natural forgetting condition of object recognition and T-maze tasks. Finally, no deleterious effect on spontaneous locomotion and general behavior was observed up to 1000 mg/kg of S 47445 given acutely in rodents, neither occurrence of convulsion or tremors. Collectively, these results indicate that S 47445 is a potent and selective AMPA-PAM presenting procognitive and potential neuroprotective properties. This drug is currently evaluated in clinical phase 2 studies in Alzheimer's disease and in Major Depressive Disorder.

摘要

S 47445是一种新型的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)受体正向变构调节剂(AMPA-PAM)。S 47445增强了谷氨酸对人和大鼠受体上AMPA受体的作用,而对NMDA受体和海人藻酸受体无活性。不同的AMPA受体亚型(GluA1/2/4翻转和非翻转变体)之间的增强作用没有差异(半数有效浓度[EC50]在2.5 - 5.4 μM之间),除了GluA4非翻转变体的EC50值较高(0.7 μM)以及对GluA1非翻转变体的增强量更大。低浓度的S 47445(0.1 μM)可缩短GluA1非翻转/GluA2翻转AMPA受体的受体反应衰减时间,并增加对谷氨酸的敏感性。此外,在重复性谷氨酸脉冲存在的情况下,S 47445(0.1和0.3 μM)可使从谷氨酸第二个脉冲开始的谷氨酸诱发电流逐渐增强,证实了S 47445在低浓度下具有快速增强作用。S 47445(1 μM)的增强作用可被选择性AMPA受体拮抗剂GYKI52466浓度依赖性地逆转,这表明S 47445对AMPA受体具有选择性调节作用。采用AMPA-海人藻酸嵌合体方法,证实S 47445与AMPA-PAMs的共同结合口袋结合。与体外对谷氨酸介导的兴奋性毒性未显示神经毒性作用相反,S 47445在10 μM时可显著保护大鼠皮质神经元。在成年啮齿动物中,按物体识别和T迷宫任务的自然遗忘条件测量,S 47445在0.3 mg/kg时可改善情景记忆和空间工作记忆。最后,在啮齿动物中急性给予高达1000 mg/kg的S 47445,未观察到对自发运动和一般行为的有害影响,也未出现惊厥或震颤。总体而言,这些结果表明S 47445是一种强效且选择性的AMPA-PAM,具有促认知和潜在的神经保护特性。该药物目前正在阿尔茨海默病和重度抑郁症的2期临床研究中进行评估。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4eaa/5590943/ada372619459/pone.0184429.g001.jpg

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