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

Serotonin (5-hydroxytryptamine, 5-HT) acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT(1e)R have confirmed roles in native tissue and are validated drug targets. Despite 5-HT(1e)R’s therapeutic potential and plausible druggability, the mechanisms of its activation...

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Autores principales: Zilberg, Gregory, Parpounas, Alexandra K., Warren, Audrey L., Fiorillo, Bianca, Provasi, Davide, Filizola, Marta, Wacker, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659432/
https://www.ncbi.nlm.nih.gov/pubmed/37986777
http://dx.doi.org/10.1101/2023.10.05.561100
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author Zilberg, Gregory
Parpounas, Alexandra K.
Warren, Audrey L.
Fiorillo, Bianca
Provasi, Davide
Filizola, Marta
Wacker, Daniel
author_facet Zilberg, Gregory
Parpounas, Alexandra K.
Warren, Audrey L.
Fiorillo, Bianca
Provasi, Davide
Filizola, Marta
Wacker, Daniel
author_sort Zilberg, Gregory
collection PubMed
description Serotonin (5-hydroxytryptamine, 5-HT) acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT(1e)R have confirmed roles in native tissue and are validated drug targets. Despite 5-HT(1e)R’s therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT(1e)R’s pharmacology in relation to the highly homologous 5-HT(1F)R, 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-HT(1e)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(1e)R and 5-HT(1F)R contribute to the agonist activity of these antidepressants.
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spelling pubmed-106594322023-11-20 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 bioRxiv Article Serotonin (5-hydroxytryptamine, 5-HT) acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT(1e)R have confirmed roles in native tissue and are validated drug targets. Despite 5-HT(1e)R’s therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT(1e)R’s pharmacology in relation to the highly homologous 5-HT(1F)R, 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-HT(1e)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(1e)R and 5-HT(1F)R contribute to the agonist activity of these antidepressants. Cold Spring Harbor Laboratory 2023-10-07 /pmc/articles/PMC10659432/ /pubmed/37986777 http://dx.doi.org/10.1101/2023.10.05.561100 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Zilberg, Gregory
Parpounas, Alexandra K.
Warren, Audrey L.
Fiorillo, Bianca
Provasi, Davide
Filizola, Marta
Wacker, Daniel
Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR
title Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR
title_full Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR
title_fullStr Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR
title_full_unstemmed Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR
title_short Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR
title_sort structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-ht1er and 5-ht1fr
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659432/
https://www.ncbi.nlm.nih.gov/pubmed/37986777
http://dx.doi.org/10.1101/2023.10.05.561100
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