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

ABSTRACT: 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. U

SUBMITTER: Zilberg G 

PROVIDER: S-EPMC11023502 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature