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Vol. 53, Issue 2, 228-233, February 1998
Pharma Division Preclinical CNS Research, F. Hoffmann-La Roche
Ltd., CH-4070 Basel, Switzerland
The in vitro binding of
[3H]LY354740, the first high affinity group II-selective
metabotropic glutamate (mGlu) receptor radioligand, was characterized
in rat cortical, hippocampal, and thalamic membranes as well as in rat
brain sections. [3H]LY354740 binding was saturable in all
regions investigated. Nonspecific binding (in the presence of 10 µM DCG-IV) was 
8% of the total. Ionotropic glutamate
receptor agonists, N-methyl-D-aspartate, (R,S)-amino-3-hydroxy-5-methyl-4-isoxazole-propionic
acid/kainate, a Na+-dependent glutamate uptake blocker as
well as a group I-selective mGlu receptor agonist (all up to 1 mM) did not inhibit [3H]LY354740 binding to
cortical membranes. However, several known metabotropic receptor
ligands inhibited the binding with the following rank order of potency:
LY354740 = LY341495 > (2S,2
R,3R)-2-(2,3-dicarboxycyclopropyl)glycine = (2S,1S,2S)-2-(2-carboxycyclopropyl)glycine > glutamate = (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid > (2S,1S,2S)-2-methyl-2-(2-carboxycyclopropyl)-glycine > quisqualate > ibotenate > L-2-amino-3-phosphonopropionic acid = (S)-
-methyl-4-carboxyphenylglycine > L-(+)-2-amino-4-phosphonobutyric acid.
N-Acetyl-aspartyl-glutamate,
(2S)--ethylglutamic acid, and
(R,S)--methyl-4-phosphonophenylglycine
inhibited [3H]LY354740 binding in a biphasic manner.
Guanosine-5-O-(3-thiotriphosphate concentration-dependently and almost completely inhibited the binding.
Finally, in parasagittal sections of rat brain, a high density of
specific binding was observed in the accessory olfactory bulb, cortical
regions (layers 1-3 > 4-6), caudate putamen, molecular layers
of the hippocampus and dentate gyrus, presubiculum, retrosplenial cortex, anteroventral thalamic nuclei, and cerebellar granular layer,
reflecting its preferential (perhaps not exclusive) affinity for
presynaptic and postsynaptic mGlu2 receptors. Thus, the pharmacology, tissue distribution, and sensitivity to
guanosine-5-O-(3-thiotriphosphate show that
[3H]LY354740 binding probably occurs to group II mGlu
receptors in rat brain.
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