Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR.
Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR.
复制标题
四环抗抑郁药对血清素受体 5-HT1eR 和 5-HT1FR 的意外激动作用的结构见解。
DOI：
10.1101/2023.10.05.561100
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Wacker,Daniel
中科院分区：
文献类型：
--
作者：
Zilberg,Gregory;Parpounas,AlexandraK;Warren,AudreyL;Fiorillo,Bianca;Provasi,Davide;Filizola,Marta;Wacker,Daniel
5-羟色胺[5-羟色胺]在人体内通过13种不同的受体起作用。在这些受体亚型中，除了5-HT1eR之外，所有这些受体亚型都已证实在天然组织中发挥作用，并成为有效的药物靶点。尽管5-HT1eR具有治疗潜力和看似合理的药效，但其激活机制仍然难以捉摸。为了阐明5-HT1eR与5-HT1FR高度同源的药理作用，我们筛选了两个受体上的胺能受体配基的文库，并观察了被称为5-HT受体泛拮抗剂的多环药物对5-HT1eR/5-HT1FR的兴奋作用。四环类抗抑郁药米安色林、西替替林和米氮平的强烈激动剂提示了它们临床观察到的抗偏头痛特性的机制。利用冷冻-EM和突变研究，我们发现并表征了Mianserin和Setitiline在5-HT1eR上独特的激动剂样结合姿势，与非活性状态5-HTR结构中的类似药物支架不同。结合计算研究，我们的数据表明，这些结合姿势以及5-HT1eR和5-HT1FR中受体特异性变构偶联有助于这些抗抑郁药的激动剂活性。
Serotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT1eR have confirmed roles in native tissue and are validated drug targets. Despite 5-HT1eR’s therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT1eR’s pharmacology in relation to the highly homologous 5-HT1FR, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT1eR/5-HT1FR agonism by multicyclic drugs described as pan-antagonists at 5-HT receptors. Potent agonism by tetracyclic antidepressants mianserin, setiptiline, and mirtazapine suggests a mechanism for their clinically observed antimigraine properties. Using cryo-EM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT1eR distinct from similar drug scaffolds in inactive-state 5-HTR structures. Together with computational studies, our data suggest that these binding poses alongside receptor-specific allosteric coupling in 5-HT1eR and 5-HT1FR contribute to the agonist activity of these antidepressants.