Identification of Anxiolytic/Nonsedative Agents among Indol-3-ylglyoxylamides Acting as Functionally Selective Agonists at the γ-Aminobutyric Acid-A (GABAA) α2 Benzodiazepine Receptor

Anxioselective agents may be identified among compounds binding selectively to the α2βxγ2 subtype of the γ-aminobutyric acid-A (GABAA)/central benzodiazepine receptor (BzR) complex and behaving as agonists or among compounds binding with comparable potency to various BzR subtypes but eliciting agonism only at the α2βxγ2 receptor. Because of subtle steric differences among BzR subtypes, the latter approach has proved much more successful. A biological screening within the class of indol-3-ylglyoxylamides 1-3 allowed us to identify compounds 1c and 2b as potential anxiolytic/nonsedative agents showing α2 selective efficacy in vitro and anxioselective effects in vivo. According to molecular modeling studies, and consistently with SARs accumulated in the past decade, 5-NO2- and 5-H-indole derivatives would preferentially bind to BzR by placing the indole ring in the LDi and the L2 receptor binding sites, respectively.