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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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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 |
Sumario: | 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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