Interactions of recombinant human histamine H1, H2, H3, and H4 receptors with 34 antidepressants and antipsychotics
Interactions of recombinant human histamine H1, H2, H3, and H4 receptors with 34 antidepressants and antipsychotics
复制标题
DOI：
10.1007/s00210-011-0704-0
复制
发表时间：
2012-02-01
影响因子：
3.6
通讯作者：
Seifert, Roland
中科院分区：
文献类型：
--
作者：
Appl, Heidrun;Holzammer, Tobias;Seifert, Roland
抗抑郁药和抗精神病药影响多个分子靶点。因此，这些药物不仅表现出独特的治疗效果，而且还表现出一些不良反应。组胺受体（H1R、H2R、H3R 和 H4R）属于 G 蛋白偶联受体大家族，是非常重要的药物靶点。所有四种 HxR 亚型均在 CNS 中表达。亲脂性、血脑屏障穿透性药物与 H(x)R 的相互作用可能有助于治疗和不良反应。因此，我们在功能测定中研究了 HxR 的效力以及 34 种抗抑郁药和抗精神病药在 HxR 上的效力和（反向）激动功效。我们在 Sf9 昆虫细胞中表达人类 H(x)R，并进行放射性配体竞争结合实验和功能稳态 GTP 酶测定。将配体亲和力和效力与文献数据进行比较并与治疗参考范围相关。几乎所有抗抑郁药和抗精神病药都表现出与 H1R 的高结合亲和力，并表现为拮抗剂。非典型抗抑郁药曲米帕明是一种高亲和力/高效 H2R 拮抗剂（pK(i), 7.39；pK(B), 7.36；pA(2), 7.55）。与 H2R 模型的对接表明了一种可能的结合模式。抗抑郁药和抗精神病药对 H3R 的亲和力较低。已知可诱导粒细胞缺乏症的非典型抗精神病药氯氮平表现出部分 H4R 激动作用，对接实验为此提供了分子基础。氯氮平还表现出 H2R 拮抗作用。我们观察到 H(x)R 的 pK(i) 和 pK(B) 值之间以及 pK(i) 和 pIC(50) 值之间的解离。抗抑郁药和抗精神病药与 H(x)R 的相互作用存在差异。功能选择性的概念（也称为配体特异性受体构象或偏向信号传导）解释了 pK(i) 和 pK(B) 值之间的解离以及 pK(i) 和 pIC(50) 值之间的差异。许多抗抑郁药和抗精神病药的 H1R 拮抗作用非常明显。曲米帕明的 H2R 拮抗作用和氯氮平的部分 H4R 激动作用可能具有临床相关性。我们还讨论了氯氮平的 H2R 拮抗作用对于该化合物引起的中性粒细胞减少症/粒细胞缺乏症的可能作用。最后，我们讨论了我们研究的方法、概念和临床局限性。
Antidepressants and antipsychotics affect multiple molecular targets. Consequently, these drugs exhibit not only unique profiles of therapeutic effects but also several undesired effects. Histamine receptors (H1R, H2R, H3R, and H4R) belong to the large family of G protein-coupled receptors and are very important drug targets. All four HxR subtypes are expressed in the CNS. Interactions of lipophilic, blood-brain barrier-penetrating drugs with H(x)Rs could contribute to therapeutic and unwanted effects. Therefore, we investigated potencies HxR as well as potencies and (inverse) agonistic efficacies of 34 antidepressants and antipsychotics at HxRs in functional assays. We expressed human H(x)Rs in Sf9 insect cells and conducted radioligand competition binding experiments and functional steady-state GTPase assays. Ligand affinities and potencies were compared with literature data and related to therapeutic reference ranges. Almost all antidepressants and antipsychotics displayed high binding affinities to H1R and behaved as antagonists. The atypical antidepressant trimipramine behaved as a high-affinity/high-potency H2R antagonist (pK(i), 7.39; pK(B), 7.36; pA(2), 7.55). Docking to an H2R model suggested a probable binding mode. The affinity of antidepressants and antipsychotics for H3R was low. The atypical antipsychotic clozapine, known to induce agranulocytosis, exhibited partial H4R agonism for which docking experiments provided a molecular basis. Clozapine also exhibited H2R antagonism. We observed dissociations between pK(i) and pK(B) values as well as between pK(i) and pIC(50) values for H(x)Rs. Antidepressants and antipsychotics interact differentially with H(x)Rs. The concept of functional selectivity (also referred to as ligand-specific receptor conformations or biased signaling) explains dissociations between pK(i) and pK(B) values as well as differences between pK(i) and pIC(50) values. The H1R antagonism of numerous antidepressants and antipsychotics is very pronounced. The H2R antagonism of trimipramine and partial H4R agonism of clozapine may be clinically relevant. We also discuss the possible role of the H2R antagonism of clozapine for neutropenia/agranulocytosis induced by this compound. Finally, we discuss the methodological, conceptual, and clinical limitations of our study.