加巴喷丁与阳离子相互作用提高其稳定性的研究  

The Interaction between Gabapentin and Cations to Improve Its Stability

作　　者：杨理想 李代禧[1] 刘宝林[1] 魏冬青[2] 郭柏松 栾翰森 奚泉 王浩 YANG Li-xiang;LI Dai-xi;LIU Bao-lin;WEI Dong-qing;GUO Bai-song;LUAN Han-sen;XI Quan;WANG Hao(Institute of Food Science and Engineering,University of Shanghai for Science and Techaology,Shanghai 200093,China;State Key Laboratory of Microbial Metabolism,Shanghai Jiaotong University,Shanghai 200240,China;Injection Laboratory,Shanghai Tofflon Science and Tecbnology Co.,Ltd.,Shanghai 201108,China;China State Institute of Pharmaceutical Industry,Shanghai 201203,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]上海交通大学微生物代谢国家重点实验室,上海200240 [3]上海东富龙科技股份有限公司注射剂实验室,上海201108 [4]中国医药工业研究总院,上海201203

出　　处：《中国药学杂志》2018年第19期1658-1666,共9页Chinese Pharmaceutical Journal

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

摘　　要：目的为了减少或抑制副反应的发生,研究在真空以及乙醇溶剂中添加不同离子前后加巴喷丁药物分子脱水缩合反应的分子机制及反应势垒。方法采用密度泛函理论(DFT)的B3LYP方法,在6-311+G (d,p)基组水平上,对添加不同离子前后的药物分子结构进行优化,计算其结构参数以及热力学参数。结果得到加入不同阳离子的反应势垒均明显高于未加入离子前的反应势垒,其中添加锌离子(Zn2+)抑制效果最好。结论证明加入不同阳离子可以有效抑制加巴喷丁缩合生成3,3-亚戊基丁内酰胺的副反应。其作用规律是通过静电作用以及改变活性基团的电子分布,提高加巴喷丁分子内缩合的反应势垒,从而抑制其副反应的发生。OBJECTIVE To reduce the occurrence of subsidiary reaction by studying the effects of different ions on the dehy- dration condensation reaction mechanism and energy barrier of gabapentin. METHODS The molecular structure of the drug be- fore and after adding different ions were optimized using the density functional theory （DFT） with B3LYP method at the 6-311 ＋ G （ d, p） basis set level, and its structural parameters and thermodynamic parameters were calculated. RESULTS The energy barriers of the subsidiary reaction obviously increased no matter what cations were added, and zinc ion was the best. CONCLU- SION It was proved that cations can effectively inhibit gabapentin from compensating to produce 3,3-pentamethylene-4-butyro- lactam. The mechanism is using proper ion to change electrostatic interaction and the electron distribution of the active groups on the reactant so as to increase the barrier of the subsidiary reaction of gabapentin, thus inhibiting the occurrence of dehydration condensation reaction.

关 键 词：密度泛函理论 加巴喷丁 反应机制 反应势垒 稳定化 

分 类 号：R942[医药卫生—药剂学]