Importance of amine pKa and distribution coefficient in the metabolism of fluorinated propranolol derivatives. Preparation, identification of metabolite regioisomers, and metabolism by CYP2D6.
Importance of amine pKa and distribution coefficient in the metabolism of fluorinated propranolol derivatives. Preparation, identification of metabolite regioisomers, and metabolism by CYP2D6.
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胺 pKa 和分配系数在氟化普萘洛尔衍生物代谢中的重要性。
DOI：
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发表时间：
2001
影响因子：
3.9
通讯作者：
W. L. Nelson
中科院分区：
文献类型：
--
作者：
A. Upthagrove;W. L. Nelson
制备了普萘洛尔和相关空间同源物的一系列 1"-单氟化、二氟化和三氟化类似物，并在重组表达的 CYP2D6 中检查了它们的代谢。这一系列化合物的结构变化，主要是在 N-异丙基的 1"-位置添加了氟和甲基，提供了 pK(a) 变化超过 5 个对数单位、亲脂性和空间变化也不同的化合物。尺寸。在代谢实验中观察到芳香族羟基化和N-脱烷基化的产物。根据产品和标准品的高压液相色谱、荧光和质谱特征，确定了 4'- 和 5'- 位芳香族羟基化的区域化学。代谢动力学参数 K(m) 和催化效率 (k(cat)/K(m)) 与添加基团的取代基参数的相关性表明，碱度增加（较高的 pK(a) 值）与酶亲和力增加（低 K(m) 值）和催化效率增加相关。与结构类似的碱性较低的氟化同系物相比，碱性更强的甲基取代化合物对 CYP2D6 显示出更高的亲和力，表明氟化化合物亲和力的降低并不是由于 N-烷基取代基的大小所致。与 log D 的相关性反映了电离程度，并表明亲脂性较低的底物（碱性较强的化合物）对 CYP2D6 具有较高的亲和力。这些结果与文献中的提议一致，即底物的质子化胺与CYP2D6活性位点的Asp301的离子配对对于底物亲和力非常重要。
A series of 1"-mono-, di-, and trifluorinated analogs of propranolol and related steric congeners was prepared, and their metabolism was examined in recombinant-expressed CYP2D6. The structural changes in this series of compounds, principally added fluorines and methyl groups in the 1"-position of the N-isopropyl group, provided compounds that varied in pK(a) by more than 5 log units and also varied in lipophilicity and in steric size. Products of both aromatic hydroxylation and N-dealkylation were observed in the metabolic experiments. The regiochemistry of aromatic hydroxylation at the 4'- and 5'-positions was assigned based on high-pressure liquid chromatography, fluorescence, and mass spectral characteristics of the products and standards. Correlations of the metabolic kinetic parameters K(m) and catalytic efficiency (k(cat)/K(m)) with substituent parameters of the added groups showed that increased basicity (higher pK(a) values) was associated with increased enzyme affinity (low K(m) values) and increased catalytic efficiency. More basic methyl-substituted compounds showed higher affinities for CYP2D6 than the structurally analogous less basic fluorinated congeners, indicating the decrease in affinity of the fluorinated compounds was not due to the size of the N-alkyl substituent. Correlations with log D reflected the degree of ionization and showed that the less lipophilic substrates (more basic compounds) had higher affinity for CYP2D6. These results are consistent with the proposal in the literature that ion pairing of the protonated amine of the substrate with Asp301 in the active site of CYP2D6 is very important to substrate affinity.
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人类 CYP2D6 及其天冬氨酸 301 --> 谷氨酸、天冬酰胺和甘氨酸突变体的活性位点拓扑。
影响因子：
3.9
作者：
Mackman,R;Tschirret-Guth,RA;Smith,G;Hayhurst,GP;Ellis,SW;Lennard,MS;Tucker,GT;Wolf,CR;OrtizdeMontellano,PR
通讯作者：
OrtizdeMontellano,PR
基于公共结合位点“分时”的 H( ) 和底物通量耦合模型。
影响因子：
2.9
作者：
Yerushalmi,H;Schuldiner,S
通讯作者：
Schuldiner,S
人肝微粒体中假外消旋普萘洛尔的代谢动力学。
DOI：
--
发表时间：
1994
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Marathe,PH;Shen,DD;Nelson,WL
通讯作者：
Nelson,WL
影响因子：
56.9
作者：
Schlichting, I;Berendzen, J;Sligar, SG
通讯作者：
Sligar, SG
影响因子：
16
作者：
Williams, PA;Cosme, J;McRee, DE
通讯作者：
McRee, DE