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bioRxiv · 10.1101/2023.10.05.561100

Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR

Zilberg, G.·Parpounas, A. K.·Warren, A. L.·Fiorillo, B.·Provasi, D.·Filizola, M.·Wacker, D.
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Abstract

Serotonin (5-hydroxytryptamine, 5-HT) acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT1eR have confirmed roles in native tissue and are validated drug targets. Despite 5-HT1eRs therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT1eRs pharmacology in relation to the highly homologous 5-HT1FR, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT1e/1FR agonism by multicyclic drugs described as pan-antagonists at 5-HT receptors. Potent agonism by tetracyclic antidepressants mianserin, setiptiline, and mirtazapine suggests a mechanism for their clinically observed anti-migraine properties. Using cryoEM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT1eR distinct from similar drug scaffolds in inactive-state 5-HTR structures. Together with computational studies, our data suggest that these binding poses alongside receptor-specific allosteric coupling in 5-HT1eR and 5-HT1FR contribute to the agonist activity of these antidepressants.

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Zilberg, G., Parpounas, A. K., Warren, A. L., Fiorillo, B., Provasi, D., Filizola, M., Wacker, D.. 2023-10-07. Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR. https://doi.org/10.1101/2023.10.05.561100

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