title: Pharmacological properties of recombinant "diazepam-insensitive" GABAA receptors.
abstract: Both native and recombinant "diazepam-insensitive" GABAA receptors (DI) are characterized by the very low affinities of prototypic 1,4-benzodiazepines such as diazepam and the high affinity of an imidazobenzodiazepine, Ro 15-4513. The presence of either an alpha 4 or alpha 6 subunit imparts this unusual pharmacological profile to DI. Based on the affinities of these compounds at recombinant DI, the pharmacological properties of alpha 4- and alpha 6-bearing receptor isoforms appear to be very similar if not identical. Using a larger sample of structurally diverse compounds, we now demonstrate distinct but related ligand binding profiles of recombinant alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 DI. Comparison of 18 ligands drawn from three principal structural groups (beta-carbolines, imidazobenzodiazepines and pyrazoloquinolinones) revealed that the affinity of at least one representative from each group differed by > 5-fold between alpha 4- and alpha 6 beta 2 gamma 2 receptors. While the high correlation (r2 = 0.926; p < 0.001) obtained between the affinities of these ligands at alpha 4- and alpha 6-containing receptors underscores the similarity between these receptor isoforms, a significant deviation of the slope of this correlation (0.792; 95% C.I. 0.673-0.911) from unity is substantive evidence that these DI possess distinct pharmacological profiles. These findings indicate that it is feasible to develop selective ligands for these DI isoforms.
authors.affiliation: Laboratory of Neuroscience, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gunnersen
authors.forename: C M
authors.initials: CM
authors.lastname: Kaufman
authors.forename: P
authors.initials: P
authors.lastname: Skolnick
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010957:Plasmids; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics; D011994:Recombinant Proteins; D014162:Transfection
chemical_list: D018757:GABA Modulators; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D003975:Diazepam