Review Article
A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model
Figure 48
The previous benzodiazepine subtype selective receptor pharmacophore models [23]. (1) The region in the α5 subtype is larger than the α1 subtypes. This is a key result. It is the principle difference between α5 subtypes compared to α2 and α3 subtypes, but especially in regard to α1 subtypes ( smaller in α1). (2) The region is larger in the α5 subtype as compared to the α1, α2, α3, α4, and α6 BzR sites. R analogs of benzodiazepines with pendant phenyls had increased affinity to α5 supporting the larger pocket in this receptor subtype, while S isomers bound to α2, α3, and α5 subtypes because of different conformational constraints.
(a) Orthogonal views of the overlap (yellow) volumes of α1β3γ2 (red) and α2β3γ2 (green) |
(b) Orthogonal views of the overlap (yellow) volumes of α2β3γ2 (red) and α3β3γ2 (green) |
(c) Orthogonal views of the overlap (yellow) volumes of α4β3γ2 (red) and α6β3γ2 (green) |
(d) Orthogonal views of the overlap (yellow) volumes of α1β3γ2 (red) and α6β3γ2 (green) |
(e) Orthogonal views of the overlap (yellow) volumes of α5β3γ2 (red) and α1β3γ2 (green) |
(f) Diazepam and the unified pharmacophore descriptors |