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Vol. 283, Issue 2, 488-493, 1997
-Aminobutyric AcidA Receptors Containing
Alpha-5 Subunits1,2
Laboratory of Neuroscience, National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health, Bethesda,
Maryland (R.J.H., C.M.C., P.S.),
New England Nuclear, Boston,
Massachusetts (S.D.H., J.D.T.), and
Department of Chemistry, University
of Wisconsin-Milwaukee, Milwaukee, Wisconsin (R.L., Q.H., J.M.C.)
The radiochemical synthesis and pharmacological properties are
described of [3H]RY 80 (ethyl-8-acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4]benzodiazepine-3-carboxylate, [ethyl-3H]). This compound is one of a
series of 8-substituted imidazobenzodiazepines that exhibits both high
affinity and selectivity for 
-aminobutyric acid (GABA)A
receptors containing alpha-5 subunits. Saturable, high-affinity (Kd ~0.7 nM)
binding of [3H]RY 80 was observed in hippocampal
membranes. The maximum number (Bmax) of
[3H]RY 80 binding sites was ~18% of that obtained with
[3H]flunitrazepam, a radioligand that labels all
"diazepam-sensitive" GABAA receptors. This value is
consistent with previous estimates (10-20%) of the proportion of rat
hippocampal GABAA receptors containing
alpha-5 subunits determined by immunoprecipitation with
selective antibodies and competition experiments using an alpha-5-selective ligand. In recombinant
GABAA receptors composed of alpha-5
beta-3 gamma-2 subunits, the
Kd of [3H]RY 80 (~0.5 nM)
was consistent with the value obtained in hippocampus, whereas the
Bmax value was not significantly different
from that obtained with [3H]flunitrazepam. The potencies
of several benzodiazepine site ligands to inhibit [3H]RY
80 binding to hippocampal membranes were in agreement with the values
obtained in recombinant (alpha-5 beta-3
gamma-2) GABAA receptors.
[3H]RY 80 was used both in a "GABA shift" assay to
correctly predict the in vivo actions of a novel,
alpha-5-selective ligand and to characterize a
population of GABAA receptors containing
alpha-5 subunits in neonatal rat cortex. These findings
demonstrate that [3H]RY 80 can be used as a radioligand
to examine the properties of GABAA receptors containing
alpha-5 subunits.
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