Evaluation of native GABA(A) receptors containing an alpha 5 subunit.
The type A receptor for gamma-aminobutyric acid (GABA), or GABA(A) receptor, is a pentamer of highly variable quaternary structure. It includes two alpha subunits, drawn from a pool of six genes, which largely determine benzodiazepine pharmacology of the receptor. In brain sections, both [(3)H]RY-80 (ethyl-8-acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4]benzodiazepine-3-carboxylate) and [(3)H]L-655,708 (ethyl (S)-11,12,13,13a-tetrahydro-7-methoxy-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate), which are selective for the benzodiazepine site of alpha 5 subunit-containing receptors, showed high-affinity, specific binding, but to fewer regions than did the nonselective benzodiazepine, [(3)H]flunitrazepam. The pattern mirrored alpha 5 mRNA distribution, and was similar to that previously reported for [(3)H]L-655,708 binding. Displacement of [(3)H]RY-80 bound to hippocampal homogenates, and of [(3)H]flunitrazepam bound to cerebellar and hippocampal homogenates showed comparable displacement by flumazenil (K(i)'s 5--7 nM). However, the K(i)'s for diazepam and for clobazam to displace [(3)H]RY-80 binding in hippocampus were about fourfold higher than for [(3)H]flunitrazepam, and the K(i) for clonazepam was sixfold larger, suggesting that these benzodiazepine receptor agonists bind with relatively lower affinity at hippocampal alpha 5-containing receptors.
Li
M
M
Department of Pharmacology, Medical College of Ohio, 3035 Arlington Ave., Toledo, OH 43614-5804, USA.
Szabo
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Rosenberg
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D000480:Alkynes; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism; D000927:Anticonvulsants / Q000378:metabolism; D001345:Autoradiography; D001569:Benzodiazepines / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D000078306:Clobazam; D002998:Clonazepam / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D005442:Flumazenil / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism; D008297:Male; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism*
D000480:Alkynes; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D007093:Imidazoles; C105490:L 655,708; D021122:Protein Subunits; C109021:RY 80; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000078306:Clobazam; D005442:Flumazenil; D002998:Clonazepam; D005445:Flunitrazepam; D003975:Diazepam