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 5a, 5c, 5e, 6, and 15j addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds 5a and 5c having ED₅₀ values of 1.2 and 1.6 mg/kg, respectively, indicating higher potency than lappaconitine (3.5 mg/kg). A metabolic analysis of compound 5e 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-dimensional quantitative structure-activity relationship (3D-QSAR) 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.

2024-08-09·Organic Letters

Structural Modification and Characteristics of Lappaconitine Alkaloid for the Discovery of Bioactive Components by Hypervalent Iodine Reagent

Article

作者: Nam, Yunchan ; Lee, Jae Yeol ; Lee, Tae-Hee ; Chang, Mun Seog ; Kang, Heung Mo ; Lim, Jiwoong ; Kim, Jiewan ; Moon, Chang Sang ; Lee, Junho

Lappaconitine, a diterpene alkaloid isolated from Aconitum sinomontanum Nakai, exhibits a wide range of biological activities, making it a promising candidate for the development of novel derivatives with therapeutic potential. In our research, we executed a two-step transformation via oxidative cleavage of lappaconitine's vicinal diol using the hypervalent iodine reagent PhI(OAc)₂, followed by strong alkaline hydrolysis. This approach yielded four new unanticipated compounds, whose structures were identified by spectroscopic methods and/or X-ray crystallography. Thus, we proposed plausible reaction mechanisms for their formations and particularly investigated the remarkable diastereoselectivity for the formation of single stereoisomer 8 observed during the alkaline hydrolysis step. Among them, compound 8 (code name: QG3030) demonstrated both enhanced osteogenic differentiation of human mesenchymal stem cells and significant osteogenic effect in an ovariectomized rat model with no acute oral toxicity.

2024-07-01·Journal of PeriAnesthesia Nursing

The Analgesic Effect of a Transdermal Lappaconitine Patch Combined With Ibuprofen Suspension for Children After Adenoidectomy and Tonsillectomy: A Randomized Clinical Trial

Article

作者: Wu, Min ; Duan, Bo ; Wang, Anken ; Xu, Jiayuan ; Ni, Yihua

PURPOSETo study the analgesic effects and side effects of a transdermal lappaconitine (TLA) patch, ibuprofen suspension (IS), and TLA combined with IS (TLACIS) after adenoidectomy and tonsillectomy.DESIGNProspective, randomized clinical trial.METHODSThe patients were randomized into three groups defined by different analgesic drug regimens: the TLA group, the IS group, and the TLACIS group. Pain scores at 2, 12, and 24 hours after surgery and adverse-event reports within the first postoperative week were collected.RESULTSUltimately, this study included 102 cases in the TLA group, 101 cases in the IS group, and 101 cases in the TLACIS group. At 2 hours after surgery, the pain scores of the TLA and the TLACIS groups were both significantly lower than that of the IS group (all P < .05). At 12 and 24 hours after surgery, the pain score of the TLACIS group was significantly lower than those of the TLA and IS groups (all P < .05); furthermore, the pain score of the IS group was significantly lower than that of the TLA group (P < .05). Within 1 week after the operation, there was no significant difference in the incidence of adverse events.CONCLUSIONSThe addition of a TLA patch can speed the onset of analgesia. In terms of analgesic effects, IS alone is more advantageous than TLA alone, while the combination of TLA and IS has the best analgesic effect. No significant differences were found in the incidence of adverse events among the three regimens.

项与高乌甲素相关的新闻（医药）

2024-07-03

·CPHI制药在线

植提 | 甲氧醉椒素或可治疗炎症性疼痛

关注并星标CPHI制药在线炎症性疼痛是什么疼痛是由实际或潜在的组织损伤所引起的一种不愉快的感觉和情感经历，发病率很高，是人们常见的困扰，几乎人人都会经历。医学上把疼痛分为伤害感受性疼痛、炎性疼痛、神经病理性疼痛、特发性疼痛与心因性疼痛以及功能性疼痛等。炎症性疼痛是其中常见的一种，是指由创伤、病毒感染以及外科手术、神经刺激、神经压迫、组织病变等原因引起引起的外周组织损伤导致炎症时所发生的疼痛，包括痛觉过敏、触诱发痛、自发痛和继发痛。炎症性疼痛影响着人们的生活质量与心理健康，严重时会影响患者日常工作能力,同时也会影响患者的精神状态,带来了全球性的医疗负担,目前治疗炎症性疼痛的药物大多副作用较多，疗效不理想，如何安全有效地止痛一直是人们关注的重要问题之一。甲氧醉椒素的由来 Piperaceae是波利尼西亚文化中的传统食用植物，俗称卡瓦，是一种多年生热带灌木，原产于太平洋群岛，使用历史超过2000 年。它分布和栽培于南太平洋地区，包括密克罗尼西亚、波利尼西亚和美拉尼西亚，传统上将根部制成粉末，在传统宗教和医药中被用作放松剂、止痛剂、肌肉松弛剂以及治疗焦虑和失眠的药物，具有镇静和抗焦虑、止痛的作用。过去十年来，在西方国家，尤其是美国、澳大利亚和欧洲越来越受欢迎，在这些国家，卡瓦以片剂或胶囊形式销售，主要用于放松和促进睡眠。其主要活性成分之一卡瓦内酯对中枢神经系统有精神作用，都是关于卡瓦内酯的镇痛作用，及其有效成分和药理机制尚不清楚，其中的甲氧醉椒素约占其生物活性的96%。研究发现卡瓦含有的甲氧醉椒素可以对抗炎性疼痛研究人员于今年5月30日发表的最新研究显示，卡瓦含有的甲氧醉椒素可以通过激活脊髓水平的CB1 受体发挥抗痛觉和抗过敏作用。在角叉菜胶诱导的大鼠爪部炎症性疼痛和坐骨神经部分结扎诱发的神经病理性疼痛中，通过鞘内注射给予雄性 Sprague-Dawley 大鼠注射甲氧醉椒素19.36 nmol/只，使用足底试验检测，以及von Frey 试验检测机械痛，发现鞘内注射甲氧醉椒素具有较强的对抗炎性疼痛的作用，注射CB1受体拮抗剂 PF 514273 可完全逆转这些效应，另一方面，另一种含量极高的卡瓦内酯卡瓦因并没有在脊髓水平发挥抗镇痛作用，这些结果为深入了解卡瓦提取物镇痛效果的决定因素提供了重要依据，证明甲氧醉椒素是卡瓦提取物中镇痛作用非常关键的成分，并有潜力成为炎症性疼痛新的治疗选择之一。我国学者也发现了许多有治疗炎性疼痛的中药成分，如芍药苷，药根碱，高乌甲素，石菖蒲等，这些植物成分可以避免既往阿片类药物、非甾体药物治疗疼痛的各种弊端，是非常值得关注的。参考文献： 1、李诗琪. 石菖蒲挥发油下调NMDAR下游通路ERK1/2-CREB-c-Fos的表达缓解大鼠炎症性疼痛诱导的痛相关情绪[D]. 广东药科大学,2021. 2、雷宝,王生海,王正梅,等. 高乌甲素通过抑制小胶质细胞活化抑制炎症性疼痛[J]. 延安大学学报（医学科学版）,2019,17(2):7-10,22. DOI:10.3969/j.issn.1672-2639.2019.02.002. 3、Chow LH, Lin PC, Chen YJ, Chen YH, Huang EY. Yangonin, one of the kavalactones isolated from Piper methysticum G. Forst, acts through cannabinoid 1 (CB1) receptors to induce an intrathecal anti-hyperalgesia. J Ethnopharmacol. 2024 May 30:118394. 来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

2022-04-25

·新浪医药新闻

国家药监局修订氢溴酸高乌甲素注射剂说明书

4月25日，国家药监局发布公告称，决定对氢溴酸高乌甲素注射剂（包括氢溴酸高乌甲素注射液、注射用氢溴酸高乌甲素、氢溴酸高乌甲素葡萄糖注射液）说明书内容进行统一修订。一、上述药品的上市许可持有人均应依据《药品注册管理办法》等有关规定，按照氢溴酸高乌甲素注射剂说明书修订要求（见附件），于2022年7月21 日前报国家药品监督管理局药品审评中心或省级药品监督管理部门备案。修订内容涉及药品标签的，应当一并进行修订；说明书及标签其他内容应当与原批准内容一致。在备案之日起生产的药品，不得继续使用原药品说明书。药品上市许可持有人应当在备案后9个月内对已出厂的药品说明书及标签予以更换。二、药品上市许可持有人应当对新增不良反应发生机制开展深入研究，采取有效措施做好药品使用和安全性问题的宣传培训，指导医师、药师合理用药。三、临床医师、药师应当仔细阅读上述药品说明书的修订内容，在选择用药时，应当根据新修订说明书进行充分的获益/风险分析。四、患者用药前应当仔细阅读药品说明书，使用处方药的，应严格遵医嘱用药。五、省级药品监督管理部门应当督促行政区域内上述药品的药品上市许可持有人按要求做好相应说明书修订和标签、说明书更换工作，对违法违规行为依法严厉查处。内容来源于网络，如有侵权，请联系删除，谢谢。

100 项与高乌甲素相关的药物交易

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