Pharmacophore/Receptor Models for GABAA/BzR Subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) via a Comprehensive Ligand-Mapping Approach

Pharmacophore/receptor models for three recombinant GABAA/BzR subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) have been established via an SAR ligand-mapping approach. This study was based on the affinities of 151 BzR ligands at five distinct (α1−3,5,6β3γ2) recombinant GABAA/BzR receptor subtypes from at least nine different structural families. Examination of the included volumes of the α1-, α5-, and α6-containing subtypes indicated that region L2 for the α5-containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region LDi, in contrast, appeared to be larger in the α1 subtype than in the other two subtypes. Moreover, region L3 in the α6 subtype is either very small or nonexistent in this diazepam-insensitive subtype (see Figure 16 for details) as compared to the other subtypes. Use of the pharmacophore/receptor models for these subtypes has resulted in the design of novel BzR ligands (see 27) selective for the α5β3γ2 receptor subtype. α5-Selective ligand 27 when ...