Characterization of the interaction of indiplon, a novel pyrazolopyrimidine sedative-hypnotic, with the GABAA receptor
Characterization of the interaction of indiplon, a novel pyrazolopyrimidine sedative-hypnotic, with the GABAA receptor
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DOI：
10.1124/jpet.104.071282
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发表时间：
2004-11-01
影响因子：
3.5
通讯作者：
Grigoriadis, DE
中科院分区：
文献类型：
--
作者：
Sullivan, SK;Petroski, RE;Grigoriadis, DE
临床上用于治疗失眠的苯二氮卓类和非苯二氮卓类镇静催眠药是通过变构增强GABA(A)受体上的抑制性神经递质GABA的作用而产生疗效的。Indiplon是一种新型的吡唑并嘧啶类镇静催眠药，目前正在开发中，用于治疗失眠。放射配基结合研究表明，Indiplon抑制[H-3]Ro15-1788(氟马西尼)与大鼠小脑和大脑皮层高亲和力膜的结合(K-I值分别为0.55和0.45 nM)。[H-3]Indiplon与大鼠小脑和大脑皮层细胞膜的结合是可逆的，具有高亲和力，K-D值分别为1.01和0.45 nM，其药理特异性与选择性标记含有α1亚基的GABA(A)受体一致。在“GABA漂移”实验和在培养的大鼠皮质神经元上对GABA诱导的氯离子电导的测量中，Indiplon是一种有效的GABA(A)受体功能的增强剂。在放射性配基结合实验和电生理实验中，Indiplon的亲和力均高于唑吡坦和扎来普隆。这些体外特性与Indiplon通过变构增强GABA(A)受体作为一种有效的镇静催眠作用的体内特性是一致的。
Clinically used benzodiazepine and nonbenzodiazepine sedative-hypnotic agents for the treatment of insomnia produce their therapeutic effects through allosteric enhancement of the effects of the inhibitory neurotransmitter GABA at the GABA(A) receptor. Indiplon is a novel pyrazolopyrimidine sedative-hypnotic agent, currently in development for insomnia. Using radioligand binding studies, indiplon inhibited the binding of [H-3]Ro 15-1788 (flumazenil) to rat cerebellar and cerebral cortex membranes with high affinity (K-i values of 0.55 and 0.45 nM, respectively). [H-3] Indiplon binding to rat cerebellar and cerebral cortex membranes was reversible and of high affinity, with K-D values of 1.01 and 0.45 nM, respectively, with a pharmacological specificity consistent with preferential labeling of GABA(A) receptors containing alpha1 subunits. In "GABA shift" experiments and in measurements of GABA-induced chloride conductance in rat cortical neurons in culture, indiplon behaved as an efficacious potentiator of GABA(A) receptor function. In both the radioligand binding and electrophysiological experiments, indiplon had a higher affinity than zolpidem or zaleplon. These in vitro properties are consistent with the in vivo properties of indiplon as an effective sedative-hypnotic acting through allosteric potentiation of the GABA(A) receptor.