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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons.
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Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons.

机译：神经递质释放增强剂利诺皮定（DuP 996）在阻断海马神经元中电压依赖性和钙激活的钾电流中的选择性。

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摘要

Linopirdine [DuP 996, 3, 3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one], a putative cognition enhancing drug, increases acetylcholine release in rat brain tissue and improves performance in animal models of learning and memory. The mechanism whereby linopirdine enhances acetylcholine release has been proposed to involve inhibition of the M-type K+ current (IM). Our study examines the selectivity of linopirdine for IM by determining its effects on other ionic currents present in rat hippocampal CA1 neurons using patch clamp techniques. Linopirdine was found to block voltage-gated, calcium-activated and leak K+ currents in a dose-dependent manner. Of the seven currents measured, linopirdine was most selective for IM with an IC50 of 2.4 +/- 0.4 microM, followed by IC (measured as a medium afterhyperpolarization tail current, ImAHP) with an IC50 of 16.3 +/- 2.4 microM. Both IM and IC were completely suppressed by linopirdine. At a concentration of 100 microM, linopirdine weakly inhibited the K+ leak current, IL, the transient outward current, IA, the delayed rectifier, IK, and the slow component of IAHP, by 28 +/- 8, 37 +/- 10, 36 +/- 9 and 52 +/- 10 percent, respectively. The mixed Na+/K+ inward rectifying current, IQ, was essentially unaffected by linopirdine (IC50 >300 microM). These results indicate that linopirdine selectively blocks IM at concentrations
机译：Linopirdine [DuP 996，3，3-双（4-吡啶基甲基）-1-苯基吲哚-2-酮]，一种公认的认知增强药物，可增加大鼠脑组织中乙酰胆碱的释放，并改善学习和记忆动物模型的性能。已提出利尼吡丁增强乙酰胆碱释放的机制涉及抑制M型K +电流（IM）。我们的研究通过使用膜片钳技术确定其对大鼠海马CA1神经元中存在的其他离子电流的影响，从而研究了利诺吡丁对IM的选择性。发现利诺吡丁以剂量依赖性方式阻断电压门控，钙激活和泄漏K +电流。在所测量的七个电流中，利诺吡丁对IM的选择性最高，IC50为2.4 +/- 0.4 microM，其次为IC（以中性超极化尾电流测量，ImAHP），IC50为16.3 +/- 2.4 microM。利尼平使IM和IC均被完全抑制。在100 microM的浓度下，利尼哌丁对K +泄漏电流IL，瞬态向外电流IA，延迟整流器IK和IAHP的缓慢成分的抑制作用为28 +/- 8、37 +/- 10，分别为36 +/- 9和52 +/- 10％。混合的Na + / K +内向整流电流IQ基本上不受利尼平（IC50> 300 microM）的影响。这些结果表明，利诺吡丁在浓度≤= 3 microM时选择性阻断IM，乙酰胆碱释放增强的近似EC50。抑制其他电压门控和钙激活的K +电流也可能有助于在中等（IC）和高（IL，IA，IK，IsAHP）浓度下利尼平提高神经递质的释放。

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