The novel anxiolytic ELB139 displays selectivity to recombinant GABA(A) receptors different from diazepam.
A chemically heterogeneous group of compounds acts at the benzodiazepine (BZ) recognition site of the diverse gamma-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 alpha1-3 or alpha5 together with any beta and the gamma2 subunit. Other compounds differentiate less, e.g. Ro15-4513, that additionally recognizes alpha4- and a6-containing receptors, or differentiate more, e.g. zolpidem, that recognizes preferentially alpha1-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 alphaibeta2gamma2 (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 alpha4-containing receptors, but it displays functional subtype specificity between alpha1, alpha2, alpha3, and alpha5beta2gamma2 receptors with highest potency in alpha3-containing receptors but highest efficacy in alpha1- or alpha2-containing receptors, respectively. ELB139 acted as a partial agonist on these receptor subtypes reaching 40-50% of the efficacy of diazepam.
Rabe
Holger
H
Laboratory of Molecular Biology, Department of Psychiatry, University of Mainz, Untere Zahlbacher Str. 8, 55131 Mainz, Germany.
Kronbach
Christiane
C
Rundfeldt
Chris
C
Lüddens
Hartmut
H
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D058785:GABA-A Receptor Agonists; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry / Q000502:physiology*; D014162:Transfection / Q000379:methods
D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D007093:Imidazoles; D010880:Piperidines; D011963:Receptors, GABA-A; C504151:1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydroimidazol-2-one; D003975:Diazepam