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Papers of the Week

Papers: 18 Nov 2023 - 24 Nov 2023

2023 Oct 07



Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT R and 5-HT R.


Zilberg G, Parpounas AK, Warren AL, Fiorillo B, Provasi D, Filizola M, Wacker D


Serotonin (5-hydroxytryptamine, 5-HT) acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT R have confirmed roles in native tissue and are validated drug targets. Despite 5-HT R’s therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT R’s pharmacology in relation to the highly homologous 5-HT R, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT R 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-HT R 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-HT R and 5-HT R contribute to the agonist activity of these antidepressants.