摘要
目的优化μ/δ阿片受体双重激动剂BVD03的合成路线,放大量合成BVD03并评价其体内外生物活性。方法采用液相合成方法,以片段缩合方式将四肽BVD03分为两个二肽片段(Boc-Dmt-N-Me-D-Ala-OH与Aba-Gly-OMe)后进行拼接,使用HATU、DIPEA作为缩合剂,得到四肽后,再将其C端酰胺化,得到目标化合物BVD03粗品,经制备型HPLC分离纯化,冻干后得到高纯度目标物BVD03。采用阿片受体激动剂钙流体外筛选模型,小鼠福尔马林疼痛模型与小鼠醋酸扭体模型对BVD03的体外受体激动及体内镇痛活性进行了评价。结果目标化合物结构经1H-NMR和HR-ESI-MS确证,HPLC纯度98.8%;所合成的BVD03显示了低纳摩尔级的体外μ/δ双重激动活性(EC50μ=4.39 nmol·L^(-1),EC50δ=0.76 nmol·L^(-1)),在两种小鼠急性炎症模型中均显示出强效且长效的镇痛活性。结论本文设计的合成路线适合放大量合成,且便于产物分离纯化,产物纯度高。BDV03可作为具有μ/δ双重激动活性的镇痛药物先导物。
The BVD03 displayed mixed μ/δ opioid agonist properties in vitro(EC50μ=1.7 pmol·L^(-1),EC50δ=16 pmol·L^(-1)).Fragment condensation of two dipeptide fragments yielded 11 using HATU and DIPEA as condensation agents.After amidation at the C-terminal of 11 and deprotection, the BVD03 was purified by semi-preparative RP-HPLC.The structure of BVD30 was confirmed by 1H-NMR and HR-ESI-MS,and the purity of the target compound reached 99.8%.Biological activity in vitro and vivo was evaluated using the opioid receptor agonist calcium flow screening model, formalin pain test and acetic acid writhing test.BVD03 showed low nanomole dual μ/δ agonism in vitro(EC50μ=4.39 nmol·L^(-1),EC50δ=0.76 nmol·L^(-1)),and possessed potent and persistent antinociceptive efficacy in two kinds of acute pathological pain test.BDV03 can be used as a lead compound for novel mixed μ/δ opioid receptor agonist.
作者
李京
张涛
任凤霞
贾红新
史卫国
LI Jing;ZHANG Tao;REN Feng-xia;JIA Hong-xin;SHI Wei-guo(Schoolof Chemical Engineering and Technology,Tianjin University,Tianjin 300350,China;State Key Laboratory of Toxicology and Medical Countermeasures,Beijing Institute of Pharmacology&Toxicology,Beijing 100850,China)
出处
《中国药物化学杂志》
CAS
CSCD
2021年第8期575-583,共9页
Chinese Journal of Medicinal Chemistry
基金
国家新药创制重大专项(2012ZX09301003-001-004)
北京市科技计划课题(Z131100002713004)。
关键词
BVD03
μ/δ阿片受体双重激动剂
多肽液相合成
生物活性评价
BVD03
μ/δopioid receptor dual agonist
liquid phase synthesis of polypeptides
evaluation of biological activity
