Psychedelic-like Properties of Quipazine and Its Structural Analogues in Mice

Known classic psychedelic serotonin 2A receptor (5-HT_2AR) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HT_2AR 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-HT_2AR as measured by [³H]ketanserin binding displacement, Ca²⁺ mobilization, and accumulation of the canonical G_q/11 signaling pathway mediator inositol monophosphate (IP₁) in vitro and in vivo. Additionally, quipazine induced via 5-HT_2AR 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-HT_2AR antagonist M100907 and absent in 5-HT_2AR 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-HT_2AR agonists at cellular signaling and behavioral pharmacology levels.