L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors
L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors
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DOI：
10.1016/j.neuropharm.2006.04.018
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发表时间：
2006-11-01
影响因子：
4.7
通讯作者：
Dawson, Gerard R.
中科院分区：
文献类型：
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作者：
Atack, John R.;Bayley, Peter J.;Dawson, Gerard R.
进一步研究了L-655，708的体外和体内性质，L-655，708是一种对GABA（A）受体具有更高亲和力的化合物，与α 1、α 2或α 3亚基相比，该化合物含有α 5亚基。该化合物对四种亚型中的每一种都具有弱的部分反向激动剂功效，但与结合数据一致，对α 5亚型具有更高的功能亲和力。在小鼠海马切片模型中，L-655，708能够增强θ爆发刺激产生的长时程增强，这与α 5亚型在涉及突触可塑性的过程（如学习和记忆）中的潜在作用一致。当以专门设计的制剂给药时，可达到相对恒定的血浆药物浓度，因此与含α 1、α 2和α 3的受体相比，可保持α 5的选择性占据（分别为75 +/- 4%和22 +/-10%），L-655，708未改变诱导癫痫发作所需的戊四唑剂量，表明L-655，708对α 5亚型的反向激动作用与促惊厥倾向无关。在Morris水迷宫中，L-655，708不仅在获取过程中而且在探测试验中增强了表现，表明该化合物具有认知增强作用。这些数据C进一步支持含α 5的GABA（A）受体作为新型认知增强药物的靶点的潜力。(c)2006年由Elsevier Ltd.出版
The in vitro and in vivo properties of L-655,708, a compound with higher affinity for GABA(A) receptors containing an alpha 5 compared to an alpha 1, alpha 2 or alpha 3 subunit have been examined further. This compound has weak partial inverse agonist efficacy at each of the four subtypes but, and consistent with the binding data, has higher functional affinity for the alpha 5 subtype. In a mouse hippocampal slice model, L-655,708 was able to enhance the long-term potentiation produced by a theta burst stimulation, consistent with a potential role for the alpha 5 subtype in processes involving synaptic plasticity, such as learning and memory. When administered in a formulation specifically designed to achieve relatively constant plasma drug concentrations, and therefore maintain selective occupancy of alpha 5- compared to alpha 1-, alpha 2- and alpha 3-containing receptors (75 +/- 4% versus 22 +/- 10%, respectively), L-655,708 did not alter the dose of pentylenetetrazole required to induce seizures, indicating that the inverse agonist effects of L-655,708 at the alpha 5 subtype are not associated with a proconvulsant liability. In the Morris water maze, L-655,708 enhanced performance not only during acquisition but also in a probe trial, demonstrating that this compound has cognition enhancing effects. These data C further support the potential of of alpha 5-containing GABA(A) receptors as a target for novel cognition enhancing drugs. (c) 2006 Published by Elsevier Ltd.