Pharmacology Identification of 5-HT2A Receptor Signaling Pathways Responsible for Psychedelic Potential

[Psychestim]

A very interesting preprint by Jason Wallach and friends.

Identification of 5-HT2A Receptor Signaling Pathways Responsible for Psychedelic Potential

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and β-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series...

www.biorxiv.org

 

[Skorpio]

This paper really does a wonderful job of showing what you can do with a modern SAR study. They make a range of novel compounds, and generate a hypothesis that 70% efficacy at Gq signaling is required for psychadelic activity.

Furthermore, using molecular docking and subsequent mutagenesis experiments, they identify a tryptophan residue that is key for biased 5HT2A receptor activation.

This paper is a very good read.

 

[ecstacylover]

Pretty neat that PLC inhibitor edelfosine was able to block HTR. Would be really compelling if it blocked psychedelic effects in humans, where it appears relatively safe in clinical trials.

Also interesting that their arrestin-biased 2A agonists were HTR-inactive, as previous work by Roth lab has shown arrestin2-KO attenuates LSD HTR (and also blocks other LSD behaviors like grooming and nose poking). Work before that showed serotonin's HTR was attenuated in arrestin2-KO whereas arrestin2-KO increased the HTR of N-methyltryptamines. All these results in C57BL/6J strain so a uniform genetic background.

So it doesn't seem to be just homeostatic changes in arrestin2-KO that are blocking HTR expression, as the N-methyltryptamines can still produce HTR in arrestin2-KO. Of course the 70% Gq hypothesis could still be consistent with some level of acute arrestin2 expression being needed for LSD HTR. Obviously serotonin has Gq efficacy >70% and is not considered psychedelic in humans (although can produce HTR), is this simply due to metabolism, insufficient concentrations, off-target effects, or is it due to yet unknown differences in its 2A activation relative to psychedelics.

Or what about something like Efavirenz? Labeled psychedelic by Hamilton Morris, produces HTR, binds 2A yet acts as an antagonist in Gq-mediated IP-1 and calcium assays (no BRET studies unfortunately).