title: Affinity of various ligands for GABAA receptors containing alpha 4 beta 3 gamma 2, alpha 4 gamma 2, or alpha 1 beta 3 gamma 2 subunits.
abstract: The potency of 30 benzodiazepine binding site ligands from 14 different structural classes for inhibition of [3H]Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4] benzodiazepine-3-carboxylate) binding to human embryonic kidney (HEK) 293 cells transiently transfected with alpha 4 beta 3 gamma 2S or alpha 1 beta 3 gamma 2S subunits of GABAA receptors was investigated. Most of these compounds were unable to significantly inhibit [3H]Ro 15-4513 binding to alpha 4 beta 3 gamma 2S receptors under conditions where they potently inhibited binding to alpha 1 beta 3 gamma 2S receptors. Nevertheless, compounds from four different structural classes were identified which exhibited a high affinity for alpha 4 beta 3 gamma 2S receptors. Variation of the structure of these compounds could lead to new ligands selectively interacting with alpha 4 beta 3 gamma 2S receptors. Compounds interacting with alpha 4 beta 3 gamma 2S receptor were also able to inhibit [3H]Ro 15-4513 binding to receptors consisting of alpha 4 gamma 2S subunits with comparable potency. These results support the conclusion that the alpha subunit is a major determinant of the benzodiazepine binding site properties of GABAA receptors containing alpha and gamma subunits.
authors.affiliation: Department of Biochemical Psychiatry, University Clinic for Psychiatry, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Scholze
authors.forename: V
authors.initials: V
authors.lastname: Ebert
authors.forename: W
authors.initials: W
authors.lastname: Sieghart
mesh_terms: D000818:Animals; D001386:Azides / Q000037:antagonists & inhibitors / Q000378:metabolism; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000378:metabolism; D001665:Binding Sites; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004622:Embryo, Mammalian; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001386:Azides; D008024:Ligands; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D001569:Benzodiazepines; C042957:Ro 15-4513