Psychedelic-like Properties of Quipazine and Its Structural Analogues in Mice.
Psychedelic-like Properties of Quipazine and Its Structural Analogues in Mice.
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DOI：
10.1021/acschemneuro.0c00291
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发表时间：
2021-03-03
影响因子：
5
通讯作者：
González-Maeso J
中科院分区：
文献类型：
--
作者：
de la Fuente Revenga M;Shah UH;Nassehi N;Jaster AM;Hemanth P;Sierra S;Dukat M;González-Maeso J
已知的经典迷幻5-羟色胺2A受体(5-HT2AR)激动剂在其结构核心保留了色胺或苯乙胺。然而，缺乏这些基本支架的药物可以诱导5-HT2AR的激活。N-取代哌嗪喹帕嗪就是这种情况。在这里，我们通过[~3H]酮丝氨酸结合置换、钙离子动员以及体内和体外典型的GQ/11信号通路介导物一磷酸肌醇(IP1)的积聚来测量奎帕嗪与5-HT2AR结合并激活5-HT2AR。此外，喹帕嗪通过5-HT2AR诱导小鼠躯体感觉皮质即刻早期基因(IEG)的表达模式与经典迷幻剂一致。在迷幻样作用的小鼠头抽动反应(HTR)模型中，奎帕嗪产生持久的效应，在峰值效应期间有较高的最大反应，该效应可被5-HT2AR拮抗剂M100907成功阻断，而在5-HT2AR基因敲除(KO)小鼠中则不存在。奎帕嗪对HTR的急性作用不受5-羟色胺耗竭的影响，不依赖于5-HT3R的激活。有趣的是，这些特征中的一些与其去氮生物等位体2-NP相同，但不被其他密切相关的哌嗪同系物所共享，这表明奎帕津可能代表着精神活性哌嗪家族中的一个不同的簇。综上所述，我们的结果增加了越来越多的证据，即奎帕嗪的特征在细胞信号和行为药理学水平上与经典迷幻5-HT2AR激动剂相匹配。
Known classic psychedelic serotonin 2A receptor (5-HT2AR) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HT2AR 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-HT2AR as measured by [3H]ketanserin binding displacement, Ca2+ mobilization, and accumulation of the canonical Gq/11 signaling pathway mediator inositol monophosphate (IP1) in vitro and in vivo. Additionally, quipazine induced via 5-HT2AR 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-HT2AR antagonist M100907 and absent in 5-HT2AR knockout (KO) mice. The acute effect of quipazine on HTR appeared to be unaffected by serotonin depletion and was independent from 5-HT3R 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-HT2AR agonists at cellular signaling and behavioral pharmacology levels.
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影响因子：
7.6
作者：
Gatch, Michael B.;Kozlenkov, Alexey;Schetz, John A.
通讯作者：
Schetz, John A.
影响因子：
7.3
作者：
Davoren, Jennifer E.;Garney, Michelle;Webb, Damien
通讯作者：
Webb, Damien
影响因子：
5
作者：
GLENNON, RA;ISMAIEL, AEM;PEROUTKA, SJ
通讯作者：
PEROUTKA, SJ
影响因子：
3.4
作者：
Dougherty, John P.;Aloyo, Vincent J.
通讯作者：
Aloyo, Vincent J.
影响因子：
6.1
作者：
GLENNON, RA;TITELER, M;MCKENNEY, JD
通讯作者：
MCKENNEY, JD