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Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT 1e R and 5-HT 1F R.

التفاصيل البيبلوغرافية
العنوان: Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT 1e R and 5-HT 1F R.
المؤلفون: Zilberg G; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Parpounas AK; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Warren AL; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Fiorillo B; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Provasi D; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Filizola M; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Wacker D; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
المصدر: Science advances [Sci Adv] 2024 Apr 19; Vol. 10 (16), pp. eadk4855. Date of Electronic Publication: 2024 Apr 17.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-
مواضيع طبية MeSH: Serotonin* , Mianserin*/pharmacology, Humans ; Antidepressive Agents ; Receptors, Serotonin/metabolism ; Signal Transduction
مستخلص: 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-HT 1e R/5-HT 1F 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 antimigraine properties. Using cryo-EM 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.
التعليقات: Update of: bioRxiv. 2023 Oct 07:2023.10.05.561100. doi: 10.1101/2023.10.05.561100. (PMID: 37986777)
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معلومات مُعتمدة: F31 MH132317 United States MH NIMH NIH HHS; T32 GM062754 United States GM NIGMS NIH HHS; R35 GM133504 United States GM NIGMS NIH HHS; S10 OD026880 United States OD NIH HHS; T32 DA053558 United States DA NIDA NIH HHS; UL1 TR004419 United States TR NCATS NIH HHS; S10 OD030463 United States OD NIH HHS; U24 GM129539 United States GM NIGMS NIH HHS
المشرفين على المادة: 333DO1RDJY (Serotonin)
250PJI13LM (Mianserin)
0 (Antidepressive Agents)
0 (Receptors, Serotonin)
تواريخ الأحداث: Date Created: 20240417 Date Completed: 20240419 Latest Revision: 20240614
رمز التحديث: 20240614
مُعرف محوري في PubMed: PMC11023502
DOI: 10.1126/sciadv.adk4855
PMID: 38630816
قاعدة البيانات: MEDLINE
الوصف
تدمد:2375-2548
DOI:10.1126/sciadv.adk4855