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

ABSTRACT: 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.

SUBMITTER: de la Fuente Revenga M

PROVIDER: S-EPMC7933111 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

de la Fuente Revenga Mario M Shah Urjita H UH Nassehi Nima N Jaster Alaina M AM Hemanth Prithvi P Sierra Salvador S Dukat Malgorzata M González-Maeso Javier J

ACS chemical neuroscience 20210105 5

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 ca ...[more]

PMID: 33400504

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Project description:Mescaline derivative (2C phenethylamines) drugs have been modified by the introduction of a N-2-methoxybenzyl group to originate a new series of compounds with recognized and potent psychedelic effects, the NBOMe-drugs. Although they are prevalent in unregulated drug markets, their toxicity profile is still poorly understood, despite several reports highlighting cases of acute intoxication, with brain and liver toxicity. Thus, in this study, mescaline, 2C-N (insertion of a nitro in the para position of the 2C phenethylamines aromatic ring) and 2C-B (insertion of a bromide in the para position of the 2C phenethylamines aromatic ring) and their corresponding NBOMe counterparts, mescaline-NBOMe, 25N-NBOMe and 25B-NBOMe, were synthetized and the in vitro neuro- and hepatocytotoxicity evaluated in differentiated SH-SY5Y and HepG2 cell lines, respectively. Cytotoxicity, oxidative stress, metabolic and energetic studies were performed to evaluate the main pathways involved in their toxicity. Our results demonstrated that the presence of the N-2-methoxybenzyl group significantly increased the in vitro cytotoxicity of 2C phenethylamines drugs in both cell lines, with the NBOMe drugs presenting lower EC50 values when compared to their counterparts. Consistently, our data showed a correlation between the drug's lipophilicity and the EC50 values, except for 2C-B. The 2C-B presented higher cytotoxic effects in both cell lines than mescaline-NBOMe, a result that can be explained by its higher passive permeability. All the NBOMe derivatives were able to cross the blood-brain barrier. Considering metabolic studies, the cytotoxicity of these drugs was shown to be influenced by inhibition of cytochrome P450 (CYP), which suggests a potential role of this enzyme complex, especially CYP3A4 and CYP2D6 isoenzymes in SH-SY5Y cells, in their detoxification or bioactivation. Furthermore, in differentiated SH-SY5Y cells, the drugs were able to induce mitochondrial membrane depolarization, and to disrupt GSH and ATP intracellular levels, these effects being concentration dependent and more pronounced for the NBOMe derivatives. No ROS overproduction was detected for any of the drugs in the tested experimental conditions. A correlation between a drug's lipophilicity and the EC50 values in both cell lines, except for 2C-B, was also obtained. In summary, the introduction of a NBOMe moiety to the parent drugs significantly increases their lipophilicity, brain permeability and cytotoxic effects, with GSH and ATP homeostasis disruption. The inhibition of CYP3A4 and CYP2D6 emphasized that CYP-mediated metabolism impacts the toxicity of these drugs.

Dataset Information

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

Publications

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

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