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 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 α5-Selective ligand 27 when injected directly into the hippocampus did enhance memory in one paradigm (Bailey et al., unpublished observations); however, systemic administration of either 9 or 27 into animals did not provide an observable enhancement. This result is in complete agreement with the observation of Liu (1996). It has been shown (Liu, 1996; Wisden et al., 1992) that in the central nervous system of the rat (as well as monkeys and pigeons) there are several native subtypes of the GABAA receptor which exhibit different functions, regional distributions, and neuronal locations. Although 27 binds more potently at α5β3γ2 receptor subtypes and is clearly an inverse agonist (Liu et al., 1996; Liu, 1996), it is possible that this ligand acts as an agonist at one or more subtypes. Liu (1996) clearly showed that a number of imidazobenzodiazepines were negative modulators at one subtype and agonists at another. Therefore, selectivity for a particular subtype at this point is not sufficient to rule out some physiological effect at other GABAA/BzR subtypes. The inability of 27 to potentiate memory when given systemically is again in support of this hypothesis, especially since α1β2γ2 subtypes are distributed throughout the brain (Wisden et al., 1992). A drug delivered systemically is far more likely to interact with all subtypes than one delivered to a specific brain region. This observation (systemic vs intrahippocampal) provides further support for the design of more subtype-specific ligands at the BzR to accurately define their pharmacology, one key to the design of new drugs with fewer side effects.