Kraus Richard L, Li Yuxing, Jovanovska Aneta, Renger John J
Sleep Research Department, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA.
Neuropharmacology. 2007 Aug;53(2):308-17. doi: 10.1016/j.neuropharm.2007.05.011. Epub 2007 May 26.
Trazodone is one of the most commonly prescribed medicines for treating depression and insomnia. However, the pharmacological mechanism of action underlying trazodone's unique effects is unclear. Despite its nanomolar affinity for 5HT(2A) receptors, histamine(1) receptors and alpha(1) adrenoceptors the drug is given at high doses to achieve clinical efficacy suggesting that other target activities may also contribute to its effects. Here we report that trazodone inhibits recombinant T-type calcium channels (Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3) in whole-cell patch-clamp studies at therapeutically relevant concentrations (IC(50)=43 microM, 45 microM, 23 microM, respectively). Inhibition was not use-dependent and showed only moderate voltage-dependence. Tonic block of Ca(v)3.1 channels held at negative membrane potentials suggested drug interaction with channels in the resting state. The major metabolite of trazodone, m-chlorophenylpiperazine, showed comparable potency on Ca(v)3.3 channels (IC(50)=35 microM) and was less active on Ca(v)3.1 channels (IC(50)=317 microM). We also demonstrate trazodone's inhibitory effects on native T-type calcium currents recorded from subthalamic neurons in a patch-clamp rat brain slice assay (approximately 30% inhibition at 100 microM). Our data suggest that T-type calcium channel antagonism may contribute to the pharmacology of trazodone and its reported neurological effects.
曲唑酮是治疗抑郁症和失眠最常用的处方药之一。然而,曲唑酮独特作用背后的药理作用机制尚不清楚。尽管该药物对5HT(2A)受体、组胺(1)受体和α(1)肾上腺素能受体具有纳摩尔亲和力,但仍需高剂量给药才能达到临床疗效,这表明其他靶点活性可能也对其作用有贡献。在此我们报告,在全细胞膜片钳研究中,曲唑酮在治疗相关浓度下(IC(50)分别为43微摩尔、45微摩尔、23微摩尔)可抑制重组T型钙通道(Ca(v)3.1、Ca(v)3.2和Ca(v)3.3)。抑制作用不依赖于使用情况,仅表现出适度的电压依赖性。在负膜电位下对Ca(v)3.1通道的持续性阻断表明药物与静息状态下的通道存在相互作用。曲唑酮的主要代谢产物间氯苯哌嗪对Ca(v)3.3通道显示出相当的效力(IC(50)=35微摩尔),而对Ca(v)3.1通道的活性较低(IC(50)=317微摩尔)。我们还在膜片钳大鼠脑片试验中证明了曲唑酮对从丘脑底核神经元记录的天然T型钙电流的抑制作用(在100微摩尔时约30%的抑制率)。我们的数据表明,T型钙通道拮抗作用可能有助于曲唑酮的药理作用及其所报道的神经学效应。