{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T15:15:14Z","timestamp":1761491714039,"version":"3.41.2"},"reference-count":40,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate analgesic active fragments were innovatively introduced at multiple sites on the benzene ring of lappaconitine. A total of 53 lappaconitine analogs were synthesized and evaluated. Compounds <jats:bold>5a<\/jats:bold>, <jats:bold>5c<\/jats:bold>, <jats:bold>5e<\/jats:bold>, <jats:bold>6<\/jats:bold>, and <jats:bold>15j<\/jats:bold> addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds <jats:bold>5a<\/jats:bold> and <jats:bold>5c<\/jats:bold> having ED<jats:sub>50<\/jats:sub> values of 1.2 and 1.6\u2009mg\/kg, respectively, indicating higher potency than lappaconitine (3.5\u2009mg\/kg). A metabolic analysis of compound <jats:bold>5e<\/jats:bold> was conducted in mice, revealing its primary metabolic processes and metabolites, and providing preliminary exploration for the druggability. Given the multiple analgesic targets of lappaconitine, its analgesic mechanism remains inconclusive. This study, for the first time, analyzed the pharmacological activity characteristics of the lappaconitine analogs using a pharmacophore model and established a three\u2010dimensional quantitative structure\u2013activity relationship (3D\u2010QSAR) to elucidate the quantitative relationship between the structures of the synthesized compounds and their analgesic activities. These findings provide valuable guidance for future structural modification and optimization of analgesic drugs.<\/jats:p>","DOI":"10.1002\/ardp.202400528","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T07:49:44Z","timestamp":1726732184000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design, synthesis, evaluation, pharmacophore modeling, and 3D\u2010QSAR of lappaconitine analogs as potential analgesic agents"],"prefix":"10.1002","volume":"357","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6046-0920","authenticated-orcid":false,"given":"Jingchuan","family":"Wu","sequence":"first","affiliation":[{"name":"School of Life Science and Engineering Southwest Jiaotong University Chengdu Sichuan China"},{"name":"Key Laboratory of Advanced Technologies of Material Minister of Education, School of Materials Science and Engineering, Southwest Jiaotong University Chengdu Sichuan 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