Pharmacophore Refinement and Lead Optimization - A study of the benzodiazepine site of the GABAA receptors

Structure activity relationship studies of synthetic flavone derivatives have been utilized to refine and evaluate a pharmacophore model of the benzodiazepine binding site of the GABAA receptors, originally developed by Zhang et al. (Drug Des. Discovery 1995, 12, 193-248). In addition to the previously proposed pharmacophore elements, two steric repulsive regions have been added to the model and the receptor region in the vicinity of the 3´-position of flavones has been characterized. The knowledge obtained in the affinity study has been used to design 5´-bromo-2´-hydroxy-6-methylflavone 53 (Ki = 0.9 nM), the highest affinity flavone derivative reported so far.

Based on the refined model, pharmacophore-guided lead optimization of 3-ethoxycarbonyl-6-trifluoromethyl-4-quinolone 58 (Ki = 122 nM), a compound previously presented by Kahnberg et al. (J. Mol. Graphics Modelling 2004, 23, 253-261), has resulted in several 4-quinolone derivatives with subnanomolar affinity. The highest affinity, Ki = 48 picomolar, is displayed by 6-benzyl-3-propylaminocarbonyl-4-quinolone 134.

Several 4-quinolone derivatives have been tested on ?1?2?2S, ?2?2?2S and ?3?2?2S GABAA receptor subtypes. All tested derivatives display a varied range of selectivity for ?1- versus ?2- and ?3-containing receptors. 6-Benzyl-3-ethoxycarbonyl-4-quinolone 121 displays the highest selectivity for ?1- versus ?3-containing receptors, by a factor of 27, of the compounds investigated in this study.