Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at α1 plus α5 versus α2 plus α3 subunits account for dissimilarities in behavioral effects in rats?

Abstract Over the last years, genetic studies have greatly improved our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA A receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA A receptors containing the α 1 subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2′N, SH-053-S-CH3-2′F, SH-053-R-CH3-2′F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of, respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA A receptors containing the α 1 subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably α 1 receptor-mediated sedative effects of GABA A modulation were not fully eliminated with any of the ligands tested, only SH-053-2′N and SH-053-S-CH3-2′F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at α 2 - and α 3 -GABA A receptors, may have been partly connected with its preferential affinity at α 5 -GABA A receptors coupled with weak agonist activity at α 1 -containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at α 1 GABA A receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at α 1 - and α 5 -GABA A receptors is sufficient for eliciting sedation.