Design of a new psychedelic quipazine analog with therapeutic efficacy and potentially fewer side effects

[u/Robert_Larsson]

https://www.science.org/doi/10.1126/scisignal.adw6055

Editor’s summary

The clinical use of serotonergic psychedelics is limited by their side effects. Younkin et al. generated a derivative (called VCU-1012) of the psychedelic quipazine with greater activity at the serotonin receptor subtype that mediates the clinically desirable effects (5-HT2AR) than at the serotonin receptor subtype responsible for the undesirable ones. Similar to quipazine, VCU-1012 exerted antidepressant and antianxiolytic effects in mice but without the gastrointestinal side effects of quipazine. Moreover, like other psychedelics, VCU-1012 increased dendritic spine density in the frontal cortex in a 5-HT2AR–dependent manner. Thus, VCU-1012 shows promise as a 5-HT2AR agonist with a more favorable side effect profile than those of typical psychedelics. —Wei Wong

Abstract

Psychedelics that target serotonin 2A receptors (5-HT2ARs) hold therapeutic promise for neuropsychiatric disorders but are often hindered by off-target actions. The 5-HT2AR agonist quipazine also activates 5-HT3R, which contributes to undesirable side effects. Here, we developed VCU-1012, a quipazine-based, structurally distinct 5-HT2AR agonist devoid of 5-HT3R activity. VCU-1012 was developed by applying a strategic chemical design that combined deconstruction to pinpoint the nitrogen atom critical for 5-HT2AR activation with structure-activity relationship studies to minimize 5-HT3R agonism. We showed that VCU-1012 modulated dendritic spine structural plasticity in the frontal cortex and produced antidepressant-like effects in mice through 5-HT2AR without activating 5-HT3R, thereby avoiding the gastrointestinal side effects of quipazine. In addition, our molecular modeling and mutant analysis suggested that VCU-1012 interacted in the canonical orthosteric binding pocket of 5-HT2AR. Together, these findings establish VCU-1012 as a potential therapeutic agent with reduced gastrointestinal impact, emphasize how differences in ligand-receptor interactions influence ligand positioning in the receptor binding pocket, and provide guidance for designing psychedelics with targeted therapeutic benefits.

[u/Robert_Larsson]

VCU-1012, also known as 1-quinazolin-2-ylpiperazine, is a psychedelic drug of the arylpiperazine family related to quipazine (1-(2-quinolinyl)piperazine).^\1])^\2])^\3]) It is a serotonin 5-HT2A receptor agonist and produces psychedelic-like effects in rodents similarly to quipazine, but lacks quipazine's serotonin 5-HT3 receptor agonism and associated adverse effects like nausea and vomiting.^\1])^\2])^\3]) The drug represents a novel structural class of psychedelics distinct from existing scaffolds.^\1])^\2])^\3])^\4])

^{https://en.wikipedia.org/wiki/VCU-1012}

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[u/Kalki_X]

Interesting, I wonder how it'll look when the HT2B affinity "issue" is dealt with. They used volinanserin to block 2A – someone should make 2A agonists based on the benzoylpiperidine fragment of volinanserin, it overlays the piperidinylindoles and tryptamines.

To be more precise it's the phenyl(piperidin-4-yl)methanone fragment. See https://doi.org/10.3390/molecules29091930

[u/Kalki_X]

Looing at the related 1-(2-Naphthyl)piperazine,  this is all bordering on a rediscovery (or renewed appreciation) of the aminotetralin motif...