{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T06:24:03Z","timestamp":1788330243875,"version":"build-2803163510"},"reference-count":77,"publisher":"American Association for the Advancement of Science (AAAS)","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82404881"],"award-info":[{"award-number":["82404881"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["spj.science.org"],"crossmark-restriction":true},"short-container-title":["Research"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    The 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    receptor is a critical target in the treatment of depression and anxiety. Bufotenine derivatives, such as 5-methoxy-\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -dimethyltryptamine (5-MeO-DMT), 5-hydroxy-\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -dimethyltryptamine (5-OH-DMT), and 5-hydroxy-\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -dimethyltryptamine\u2014derived from traditional Chinese medicine\u2014have shown antidepressant potential. However, the structural basis of their interaction with 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    and their pharmacological profiles remain incompletely understood. This study investigated bufotenine derivatives acting on multiple serotonin receptors, highlighting 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    as a key mediator of antidepressant effects while recognizing 5-HT\n                    <jats:sub>2A<\/jats:sub>\n                    as primarily responsible for hallucinogenic outcomes, to identify candidates with therapeutic efficacy but reduced hallucinogenic liability. We determined the cryo-electron microscopy structures of 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    bound to selected bufotenine derivatives. Functional assays in mice, including behavioral tests and receptor activation studies, were used to evaluate the antidepressant of each compound. Structural analysis revealed that all bufotenine derivatives engage conserved motifs within the 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    binding pocket, with 5-OH-DMT displaying a distinct interaction pattern. Behavioral assays showed that 5-OH-DMT and 5-MeO-DMT retained strong antidepressant and anxiolytic effects. These pharmacological differences correlate with their unique receptor binding conformation. This study delineated the structural pharmacology of bufotenine derivatives at the 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    receptor, identifying 5-OH-DMT and 5-MeO-DMT as promising antidepressant and anxiolytic candidates. The findings establish a molecular framework for the development of next-generation nonhallucinogenic therapeutics aimed at 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    .\n                  <\/jats:p>","DOI":"10.34133\/research.0987","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T05:30:10Z","timestamp":1761283810000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":2,"title":["Structural Pharmacology of Bufotenine Derivatives in Activating the 5-HT\n                    <sub>1A<\/sub>\n                    Receptor for Therapeutic Potential in Depression and Anxiety"],"prefix":"10.34133","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4048-5044","authenticated-orcid":false,"given":"Shu-jie","family":"Li","sequence":"first","affiliation":[{"name":"Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, College of Pharmacy, \rNanjing University of Chinese Medicine, Nanjing 210023, China."},{"name":"Department of Traditional Chinese Medicine, \rFujian Medical University Union Hospital, Fuzhou 350000, Fujian, China."},{"name":"State Key Laboratory of Drug Research, \rShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-ning","family":"Yuan","sequence":"additional","affiliation":[{"name":"Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, College of Pharmacy, \rNanjing University of Chinese Medicine, Nanjing 210023, China."},{"name":"State Key Laboratory of Drug Research, \rShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, 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