Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT1eR and 5-HT1FR

Zilberg, Gregory; Parpounas, Alexandra K.; Warren, Audrey L.; Fiorillo, Bianca; Provasi, Davide; Filizola, Marta; Wacker, Daniel

doi:10.1126/sciadv.adk4855

Title: Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT_1eR and 5-HT_1FR

Journal Article · 16 April 2024 · Science Advances

DOI: https://doi.org/10.1126/sciadv.adk4855 · OSTI ID:2470310

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Icahn School of Medicine at Mount Sinai, New York, NY (United States)

Serotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT_1eR have confirmed roles in native tissue and are validated drug targets. Despite 5-HT_1eR’s therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT_1eR’s pharmacology in relation to the highly homologous 5-HT_1FR, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT_1eR/5-HT_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 antimigraine properties. Using cryo-EM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT_1eR 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_1eR and 5-HT_1FR contribute to the agonist activity of these antidepressants.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States). Laboratory for BioMolecular Structure (LBMS)

Sponsoring Organization:: National Institutes of Health (NIH); Simons Foundation; USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: SC0012704

OSTI ID:: 2470310

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 16 Vol. 10; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT1eR and 5-HT1FR

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Title: Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT_1eR and 5-HT_1FR