Tebib S, Bourguignon J J, Wermuth C G
Department of Molecular Pharmacochemistry, CNRS et Unité 44 de l'INSERM, Strasbourg, France.
J Comput Aided Mol Des. 1987 Jul;1(2):153-70. doi: 10.1007/BF01676959.
Applied to seven potent benzodiazepine-receptor ligands belonging to chemically different classes, the active analog approach allowed the stepwise identification of the pharmacophoric pattern associated with the recognition by the benzodiazepine receptor. A unique pharmacophore model was derived which involves six critical zones: (a) a pi-electron rich aromatic (PAR) zone; (b) two electron-rich zones delta 1 and delta 2 placed at 5.0 and 4.5 A respectively from the reference centroid in the PAR zone; (c) a freely rotating aromatic ring (FRA) region; (d) an out-of-plane region (OPR), strongly associated with agonist properties; and (e) an additional hydrophobic region (AHR). The model accommodates all presently known ligands of the benzodiazepine receptor, identifies sensitivity to steric hindrance close to the delta 1 zone, accounts for R and S differential affinities and distinguishes requirements for agonist versus non-agonist activity profiles.
将活性类似物方法应用于七种化学类别不同的强效苯二氮䓬受体配体，逐步确定了与苯二氮䓬受体识别相关的药效团模式。由此得出了一个独特的药效团模型，该模型涉及六个关键区域：(a) 富π电子芳香（PAR）区；(b) 两个富电子区δ1和δ2，分别位于PAR区中距参考质心5.0 Å和4.5 Å处；(c) 一个可自由旋转的芳香环（FRA）区域；(d) 一个与激动剂特性密切相关的面外区域（OPR）；以及(e) 一个额外的疏水区域（AHR）。该模型涵盖了目前所有已知的苯二氮䓬受体配体，确定了靠近δ1区对空间位阻的敏感性，解释了R和S的不同亲和力，并区分了激动剂与非激动剂活性谱的要求。
