μ型阿片受体拮抗剂化学反应性指数的量子化学计算

Quantum Chemical Calculations on Chemical Reactivity Index of μ-Opioid Receptor Antagonist

摘要: μ型阿片受体拮抗剂在临床上具有越来越广泛的应用，量子化学计算的评估方法在提高化合物设计效率、减少合成工作量上也发挥着更加重要的作用。拮抗剂1-(2-环己基乙基)-4-(氮-2-呋喃甲酰基-氮-(5-甲基吡啶-2)氨基)哌啶具有较好的拮抗活性，本论文以其为结构基础，设计出12个目标化合物，通过基于量子化学从头计算法的理论计算获得最低能量构象和亲核性反应指数(化学势变化率和福井函数值)，同时预测在4-位取代基一定时，1-位环己基系列化合物活性最强，苯乙基、噻吩基、乙烯基系列化合物活性依次减弱。后续工作中将与实际动物实验结果相比较，确立较优的理论算法，并构建出合理的构效关系模型方程，为以后的化合物设计合成提供理论指导。

Abstract: μ-opioid receptor antagonist is more and more widely used in clinical practice, and quantum che-mistry calculations on compounds design to improve efficiency and reduce synthesis workload also play an important role. This paper designed 12 target compounds based on the structure of antagonist 1-(2-cyclohexylethyl)-4-(N-2-furoyl-N-(5-methylpy-ridin-2-yl) amino) piperidine which has good antagonist activities, and calculated the lowest energy conformations and nucleophilic reactions index (the chemical potential change rate and Fukui function value) by the quantum chemical ab initio method. In this paper, it predicted that when the substituents at the fourth posi-tion are the same, the sequence of compound activity is 1-cyclohexylseries compound, 1-phene- thylseries compound, 1-thiopheneseries compound and 1-vinylseries compound, in which 1-cyc- lohexylseries compound is the strongest. In the later work, we will compare the results with the actual results of animal experiments to establish an optimum theory algorithm, and build a rea-sonable QSAR model equation to provide theoretical guidance for the future compounds synthesis.