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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo
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The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo

机译：肾上腺素能受体拮抗剂Carvedilol在体外和体内与血清素2a受体相互作用

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There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.
机译：对潜在的临床应用越来越高，化合物与血清素2a（5-HT2A）受体相互作用。因此，探索与5-HT2A受体相互作用的新化合物是有意思的。在本研究中，我们使用计算化学来鉴定5-HT2A受体结合和功能的关键配体结构特征。使用那些配体特征的复合数据库查询揭示了肾上腺素能受体拮抗剂Carvedilol作为高优先级匹配。由于Carvedilol临床上用于心血管疾病，我们进行了实验以评估它是否具有与5-HT2A受体的任何相互作用。体外实验证明，Carvedilol对5-HT2A受体具有高纳摩尔亲和力。在体内实验中表明，卡维地洛增加了乙醇诱导的抗反射损失，抑制了小鼠的响应的操作剂，并且这些效果通过用选择性5-HT2A受体拮抗剂M100907进行预处理而衰减。此外，卡维地洛没有诱导小鼠的头部抽搐反应，表明缺乏荧光效果。然而，Carvedilol没有激活规范化5-HT2A受体信号传导途径和拮抗的血清素介导的信号传导。它还减少了由2,5-二甲氧基-4-碘胺苯丙胺，表明体内拮抗作用，变构调制或功能偏压的潜力诱导的头排腹响应。这些数据表明卡维地洛与5-HT2A受体具有功能相关的相互作用，为临床使用的化合物提供了一种新的作用机制。然而，我们的研究结果不明确描绘卡维地洛在5-HT2A受体的精确作用机制，并且需要额外的实验来阐明5-HT2A受体在卡维地洛的行为和临床作用中的作用。

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