From Methaqualone and Beyond: Structure-Activity Relationship of 6-, 7-, and 8-Substituted 2,3-Diphenyl-quinazolin-4(3)-ones and in Silico Prediction of Putative Binding Modes of Quinazolin-4(3)-ones as Positive Allosteric Modulators of GABA Receptors.

Methaqualone (2-methyl-3-(-tolyl)-quinazolin-4(3)-one, MTQ) is a moderately potent positive allosteric modulator (PAM) of GABA receptors (GABARs). In a previous structure-activity relationship (SAR) study probing the importance of 2- and 3-substituents in the quinazolin-4(3)-one scaffold, several potent GABAR PAMs were identified, including 2,3-diphenylquinazolin-4(3)-one (PPQ) and 3-(2-chlorophenyl)-2-phenylquinazolin-4(3)-one (Cl-PPQ). Here, PPQ was applied as lead in a SAR study of 6-, 7-, and 8-substituents in the quinazolin-4(3)-one by synthesis and functional characterization of 36 PPQ analogs at various GABAR subtypes. While none of the new analogs were significantly more potent than PPQ or displayed pronounced subtype selectivity across the GABARs tested, several interesting SAR observations were extracted from the study. In an study, the putative binding modes of MTQ, PPQ, and Cl-PPQ in the transmembrane β/α interface of the αβγ GABAR 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.