Methaqualone (2-methyl-3-(o-tolyl)-quinazolin-4(3H)-one, MTQ) is a moderately potent positive allosteric modulator (PAM) of GABA_A receptors (GABA_ARs). In a previous structure–activity relationship (SAR) study probing the importance of 2- and 3-substituents in the quinazolin-4(3H)-one scaffold, several potent GABA_AR PAMs were identified, including 2,3-diphenylquinazolin-4(3H)-one (PPQ) and 3-(2-chlorophenyl)-2-phenylquinazolin-4(3H)-one (Cl-PPQ). Here, PPQ was applied as lead in a SAR study of 6-, 7-, and 8-substituents in the quinazolin-4(3H)-one by synthesis and functional characterization of 36 PPQ analogs at various GABA_AR subtypes. While none of the new analogs were significantly more potent than PPQ or displayed pronounced subtype selectivity across the GABA_ARs tested, several interesting SAR observations were extracted from the study. In an in silico study, the putative binding modes of MTQ, PPQ, and Cl-PPQ in the transmembrane β₂⁽⁺⁾/α₁⁽⁻⁾ interface of the α₁β₂γ_2S GABA_AR were predicted. Several plausible binding modes were identified for the three PAMs, and rationalization of the molecular basis for their different modulatory potencies was attempted.

中文翻译：

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从甲喹酮和超越：6-构效关系，7-和8-取代的2,3-二苯基-喹唑啉-4（3 H ^） -酮和在推定的结合喹唑啉-4-的模式硅铝预测（3 ħ）-作为GABA _A受体的正变构调节剂

甲基苯二甲酮（2-甲基-3-（邻甲苯基）-喹唑啉-4（3 H）-one，MTQ）是GABA _A受体（GABA _A Rs）的中度有效正变构调节剂（PAM ）。在先前的结构-活性关系（SAR）研究中，研究了喹唑啉-4（3 H）-一个支架中2-和3-取代基的重要性，确定了几种有效的GABA _A R PAM，包括2,3-二苯基喹唑啉- 4（3 H）-1（PPQ）和3-（2-氯苯基）-2-苯基喹唑啉-4（3 H）-1（Cl-PPQ）。在这里，PPQ被用作喹唑啉4（3 H中的6、7和8个取代基的SAR研究的先导）-通过合成和功能表征36种不同GABA _A R亚型的PPQ类似物。尽管没有一个新的类似物比PPQ具有更强的效力或在测试的GABA _A Rs上显示出明显的亚型选择性，但从这项研究中提取了一些有趣的SAR观察结果。在一个在硅片的研究中，在跨膜MTQ，PPQ，和Cl-PPQ的推定的结合模式β ₂ ^（+） /α ₁ ^{（ - ）}的α的接口₁ β ₂ γ _2S GABA_甲R被预测。确定了三个PAM的几种可能的结合模式，并试图合理化其不同调节潜能的分子基础。