Allen M S, LaLoggia A J, Dorn L J, Martin M J, Costantino G, Hagen T J, Koehler K F, Skolnick P, Cook J M
Department of Chemistry, University of Wisconsin-Milwaukee 53201.
J Med Chem. 1992 Oct 30;35(22):4001-10. doi: 10.1021/jm00100a004.
The synthesis and affinities of six new 3-substituted beta-carbolines (6-10, 12) for the benzodiazepine receptor (BzR) are described. These analogs were used both to probe the dimensions of the hydrophobic pocket in the benzodiazepine receptor and to test the predictive ability of a previously reported 3D-QSAR regression model. Of the new analogs synthesized, the gamma-branched derivatives (isobutoxy, 7, IC50 = 93 nM; isopentoxy, 9, IC50 = 104 nM) display significantly higher affinity for the BzR than either the beta-branched (sec-butoxy, 6, IC50 = 471 nM; tert-butyl ketone, 12, IC50 = 358 nM) or delta-branched (isopentoxy, 8, IC50 = 535 nM) analogs. An exception to this rule is the gamma-branched 3-benzyloxy derivative 10 (IC50 > 1000 nM) which appears to have a chain length that is too long to be accommodated by the BzR. The standard error of prediction for these six new beta-carbolines using the original regression model is significantly lower than the standard error estimate of the cross validation runs on the training set, hence the predictions made using this model are much better than expected. In order to obtain more credible predictions, a new procedure called GOLPE (generating optimal linear PLS estimates) was used to eliminate irrelevant electrostatic and steric descriptors from the regression equation. A substantial reduction in the standard error estimate resulted. The predictions from this new regression equation were somewhat less accurate than the ones obtained with the original regression equation; however the standard error of prediction and the standard error estimate are in much closer agreement. Finally, to probe the effect that the quality of the steric and electrostatic potentials has on 3D-QSAR analyses, the semiempirical MNDO parallel PRDDOE geometries and Mulliken charges used in the original analyses were replaced with ab initio 3-21G parallel 6-31G* geometries and electrostatic potential fit charges. A modest decrease in the standard error estimate and increase in cross validated R2 resulted.
描述了六种新的3-取代β-咔啉（6 - 10、12）与苯二氮䓬受体（BzR）的合成及亲和力。这些类似物既用于探究苯二氮䓬受体中疏水口袋的尺寸，也用于测试先前报道的三维定量构效关系（3D - QSAR）回归模型的预测能力。在合成的新类似物中，γ - 支链衍生物（异丁氧基，7，IC50 = 93 nM；异戊氧基，9，IC50 = 104 nM）对BzR的亲和力明显高于β - 支链（仲丁氧基，6，IC50 = 471 nM；叔丁基酮，12，IC50 = 358 nM）或δ - 支链（异戊氧基，8，IC50 = 535 nM）类似物。该规则的一个例外是γ - 支链的3 - 苄氧基衍生物10（IC50 > 1000 nM），其链长似乎过长，无法被BzR容纳。使用原始回归模型对这六种新β - 咔啉进行预测的标准误差显著低于对训练集进行交叉验证运行时的标准误差估计值，因此使用该模型进行的预测比预期要好得多。为了获得更可靠的预测，采用了一种名为GOLPE（生成最优线性偏最小二乘估计）的新程序，从回归方程中消除无关的静电和空间描述符。标准误差估计值大幅降低。新回归方程的预测结果比原始回归方程的预测结果略不准确；然而，预测标准误差和标准误差估计值的一致性要好得多。最后，为了探究空间和静电势的质量对3D - QSAR分析的影响，将原始分析中使用的半经验MNDO平行PRDDOE几何结构和Mulliken电荷替换为从头算3 - 21G平行6 - 31G*几何结构和静电势拟合电荷。标准误差估计值略有下降，交叉验证的R2有所增加。
