3-甲基芬太尼衍生物立体异构体的 QSAR 研究

用比较分子力场分析(CoMFA)方法研究了3-甲基芬太尼和羟甲芬太尼立体异构体的三维定量构效关系(3D-QSAR)。所得CoMFA-QSAR模型有很好的预测能力(γ²_{cros-validated}=0.716,n_{optimalcomponent}=5,γ²_conventional=0.999,s=0.052,F=1305.1),模型中,被研究化合物的构象可能就是其活性构象。以AM1方法进行量子化学计算,获得上述可能活性构象的结构参数及空间位置参数。基于这些参数,用偏最小二乘法(PLS)获得了被研究化合物的QSAR方程。所得PLS-QSAR模型具有较好的预测能力,并且显示被研究化合物的镇痛活性取决于分子中负电性的哌啶氮原子(N_PA)净电荷以及哌啶氮原子、羰基氧原子、1-β-苯环、4-N-苯环、3-甲基和2′-羟基的空间位置。

STUDIES ON QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF THE STEREOISOMERS OF 3-METHYLFENTANYL DERIVATIVES

Comparative molecular field analysis (CoMFA) method was used to study the three dimensional structure activity relationship (3D-QSAR) of the stereoisomers of 3-methylfentanyl and ohmefentanyl. The CoMFA QSAR model has very good predictive ability (γ²_{cross-validated} =0.716, n_{optimal component} =5,γ²_conventional =0.999, s=0.052, F=1305.1), in which the conformations of the studied compounds could be their possibly bioactive conformations. By quantum chemical calculation (AM1), the structural and stereo parameters of the above possibly bioactive conformations were obtained. On the basis of these parameters, the QSAR equations of the studied compounds were derived by partial least squares (PLS) method. The PLS-QSAR model with better predictive ability showed that, the analgesic activity is closely dependent on the net charge of nitrogen atom in piperidine (N_PA) as well as the geometric parameters of N_PA, O_PA, 1-β -henyl ring, 4-N-phenyl ring, 3-methyl and 2′-hydroxyl.