The novel anxiolytic ELB139 displays selectivity to recombinant GABAA receptors different from diazepam

Abstract A chemically heterogeneous group of compounds acts at the benzodiazepine (BZ) recognition site of the diverse γ-aminobutyric acid type A (GABA A ) receptor complexes which can assemble from more than 16 known subunits. Most 1,4-BZs like diazepam recognize all GABA A /BZ receptors containing the α1–3 or α5 together with any β and the γ2 subunit. Other compounds differentiate less, e.g. Ro15-4513, that additionally recognizes α4- and a6-containing receptors, or differentiate more, e.g. zolpidem, that recognizes preferentially α1-containing receptors. Here we describe the functional properties of 1-(4-chloro-phenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on (ELB139) in the presence and absence of the BZ receptor antagonist flumazenil (Ro15-1788) on recombinant α i β2γ2 ( i  = 1–5) receptor subtypes expressed in HEK 293 cells. The properties were measured with the whole-cell variation of the patch-clamp technique and compared to those of diazepam. Like the latter, ELB139 did not potentiate GABA-induced currents in α4-containing receptors, but it displays functional subtype specificity between α1, α2, α3, and α5β2γ2 receptors with highest potency in α3-containing receptors but highest efficacy in α1- or α2-containing receptors, respectively. ELB139 acted as a partial agonist on these receptor subtypes reaching 40–50% of the efficacy of diazepam.