Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, United States.
Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia 23219, United States.
ACS Chem Neurosci. 2021 Mar 3;12(5):831-844. doi: 10.1021/acschemneuro.0c00291. Epub 2021 Jan 5.
Known classic psychedelic serotonin 2A receptor (5-HTR) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HTR can be elicited by drugs lacking these fundamental scaffolds. Such is the case of the N-substituted piperazine quipazine. Here, we show that quipazine bound to and activated 5-HTR as measured by [H]ketanserin binding displacement, Ca mobilization, and accumulation of the canonical G signaling pathway mediator inositol monophosphate (IP) and . Additionally, quipazine induced via 5-HTR an expression pattern of immediate early genes (IEG) in the mouse somatosensory cortex consistent with that of classic psychedelics. In the mouse head-twitch response (HTR) model of psychedelic-like action, quipazine produced a lasting effect with high maximal responses during the peak effect that were successfully blocked by the 5-HTR antagonist M100907 and absent in 5-HTR knockout (KO) mice. The acute effect of quipazine on HTR appeared to be unaffected by serotonin depletion and was independent from 5-HTR activation. Interestingly, some of these features were shared by its deaza bioisostere 2-NP, but not by other closely related piperazine congeners, suggesting that quipazine might represent a distinct cluster within the family of psychoactive piperazines. Together, our results add to the mounting evidence that quipazine's profile matches that of classic psychedelic 5-HTR agonists at cellular signaling and behavioral pharmacology levels.
已知经典的血清素 2A 受体（5-HTR）激动剂在其结构核心保留了色胺或苯乙胺。然而，激活 5-HTR 可以通过缺乏这些基本支架的药物来引发。N-取代哌嗪喹嗪就是这种情况。在这里，我们表明，喹嗪与 5-HTR 结合并激活，如[H]酮色林结合位移、Ca 动员以及经典 G 信号通路介体肌醇单磷酸（IP）和 的积累所测量的。此外，喹嗪通过 5-HTR 诱导了与经典迷幻药一致的小鼠体感皮层中的即刻早期基因（IEG）表达模式。在迷幻样作用的小鼠头部抽搐反应（HTR）模型中，喹嗪产生了持久的效果，在峰值效应期间具有高最大反应，这些反应被 5-HTR 拮抗剂 M100907 成功阻断，并且在 5-HTR 敲除（KO）小鼠中不存在。喹嗪对 HTR 的急性作用似乎不受血清素耗竭的影响，并且与 5-HTR 激活无关。有趣的是，其去氮生物等排体 2-NP 具有其中一些特征，但其他密切相关的哌嗪同系物则没有，这表明喹嗪可能代表了精神活性哌嗪家族中的一个独特簇。总之，我们的结果增加了越来越多的证据，表明喹嗪的特征在细胞信号和行为药理学水平上与经典迷幻 5-HTR 激动剂相匹配。
