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At present, modulators with heightened selectivity for a subtype of LVGCCs are still highly desired. In this study we explored three classes of <jats:italic>Buxus<\/jats:italic> alkaloids and identified 9(10\/19)abeo\u2010artanes Buxusemine H and Buxusemine L (BXSL) as an unprecedented type of Ca<jats:sub>v<\/jats:sub>3.2 inhibitors. Particularly, BXSL exhibited Ca<jats:sub>v<\/jats:sub>3.2 inhibition comparable to Z944, a non\u2010subtype\u2010selective LVGCCs inhibitor under clinical trial. While lacking specificity for Ca<jats:sub>v<\/jats:sub>3.3, BXSL showed a 30\u2010fold selectivity of Ca<jats:sub>v<\/jats:sub>3.2 over Ca<jats:sub>v<\/jats:sub>3.1. As compared to several well\u2010known inhibitors, the experimental and computational studies suggested BXSL exhibits a distinct binding mode to Ca<jats:sub>v<\/jats:sub>3.2, notably through the essential interaction with serine\u20101543 in domain III. Furthermore, BXSL showed minimal impact on various recombinant and native nociceptive ion channels, while significantly reducing the excitability of isolated mouse dorsal root ganglion neurons. Animal studies in wild\u2010type and Ca<jats:sub>v<\/jats:sub>3.2 knock\u2010out mice revealed that BXSL (5\u2005mg\/kg), by inhibiting Ca<jats:sub>v<\/jats:sub>3.2, exhibits an analgesic effect equivalent to Z944 (10\u2005mg\/kg) or mibefradil (10\u2005mg\/kg). Moreover, we proposed a structural rationale for the high selectivity of 9(10\/19)abeo\u2010artane\u2010type alkaloids towards Ca<jats:sub>v<\/jats:sub>3.2 over Ca<jats:sub>v<\/jats:sub>3.1. This study introduces a novel analgesic agent and valuable molecular insight for structure\u2010based innovative Ca<jats:sub>v<\/jats:sub>3.2 drug development.<\/jats:p>","DOI":"10.1002\/anie.202313461","type":"journal-article","created":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T05:18:25Z","timestamp":1700803105000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Analgesic <i>Buxus<\/i> alkaloids with Enhanced Selectivity for the Low\u2010Voltage\u2010Gated Calcium Channel Ca<sub>v<\/sub>3.2\u2009over Ca<sub>v<\/sub>3.1\u2009through a New Binding Mode"],"prefix":"10.1002","volume":"63","author":[{"given":"Ye","family":"Gong","sequence":"first","affiliation":[{"name":"State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of Botany Chinese Academy of Sciences  Kunming 650201 Yunnan P. R. 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