α-、β-环糊精对加巴喷丁的包合作用及其稳定性的理论研究  

Theoretical research on the stabilization of gabapentin by inclusion of α- and β -cyclodextrin

作　　者：杨理想 李代禧[1] 栾翰森 郭柏松 魏冬青[4] 王浩 YANG Li-Xiang;LI Dai-Xi;LUAN Han-Sen;GUO Bai-Song;Wei Dong-Qing;WANG Hao(Institute of Food Science and Engineering,University of Shanghai for Science and Technology,Shanghai 200093,China;China State Institute of Pharmaceutical Industry,Shanghai 201203,China;Injection Laboratory,Shanghai Tofflon Science and Technology Co,Ltd.,Shanghai 201108,China;State Key Laboratory of Microbial Metabolism,Shanghai Jiao Tong University,Shanghai 200240,China)

机构地区：[1]上海理工大学食品科学与工程研究所,上海200093 [2]中国医药工业研究总院,上海201203 [3]上海东富龙科技股份有限公司注射剂实验室,上海201108 [4]上海交通大学微生物代谢国家重点实验室,上海200240

出　　处：《原子与分子物理学报》2019年第3期361-372,共12页Journal of Atomic and Molecular Physics

基　　金：上海市重点学科项目(T0503,P0502);上海市“创新行动计划”国际科技合作项目(12430702000);上海市自然科学基金(12ZR1420400)

摘　　要：加巴喷丁作为新一代抗癫痫药物的代表,具有口服吸收快、毒副作用小、治疗效果好等诸多优点,但由于其容易脱水缩合形成具有一定毒性的3,3-亚戊基丁内酰胺,导致药物制剂生产受到部分限制.为了减少或抑制副反应的发生,本文采用密度泛函理论(DFT)的B3LYP方法,研究在真空以及水溶液中α-、β-环糊精包合加巴喷丁药物分子的过程,以及加巴喷丁在环糊精空腔中脱水缩合反应的分子机制及反应势垒.结果表明:在真空以及水溶液中α-、β-环糊精与加巴喷丁都能够形成较为稳定的包合物,但β-环糊精包合效果更优;而且包合后,加巴喷丁在环糊精空腔中的自身缩合势垒显著升高,特别是包合物B-β-CD s(氨基质子化类型的加巴喷丁的活性基团与β-环糊精小口端结合并且其六元环置于环糊精空腔中),其势垒在真空以及水溶液中分别达到了331.353 kJ/mol、283.538 kJ/mol,远高于包合前的127.86 kJ/mol、137.88 kJ/mol.由此,证明α-、β-环糊精对加巴喷丁的包合作用可以有效抑制加巴喷丁缩合生成内酰胺的副反应.Gabapentin as a representative of a new generation of antiepileptic drugs,with fast oral absorption,weak side effect,good treatment effect and many other advantages.However,because of its easy dehydration condensation to form slightly toxic 3,3-Pentamethylene-4-butyrolactam,which results in partial restriction on the production of pharmaceutical preparations.In order to reveal the occurrence of subsidiary reaction,the density functional theory(DFT)with B3 LYP method and 6-31 G(d)basis set is used to study on the inclusion processes of gabapentin withα-cyclodextrin,β-cyclodextrin and the effect of inclusive complexes on the dehydration condensation reaction mechanism and energy barrier of gabapentin.Modeling results showed that theα-cyclodextrin,β-cyclodextrin and gabapentin can form stable inclusive complexes in vacuum and water,but the inclusive effect ofβ-cyclodextrin is better;After inclusion,the self-condensation potential barrier of gabapentin in the cyclodextrin cavity is significantly increased.Especially,the inclusive complex B-β-CD_s(a protonated active group of gabapentin with the small mouth ofβ-cyclodextrin and its hexatomic ring in the cavity of cyclodextrin),reaction barriers reach 331.353 kJ/mol and 283.538 kJ/mol,respectively,in vacuum and water,much higher than 127.86 kJ/mol and 137.88 kJ/mol before inclusion.Thus,the inclusion of gabapentin byα-cyclodextrin,β-cyclodextrin was shown to effectively inhibit the side reactions of gabapentin.

关 键 词：密度泛函理论 加巴喷丁 α-、β-环糊精 包合物 反应势垒 稳定化 

分 类 号：O64[理学—物理化学]