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Characterization of [ 3 H]‐(2S,2′R,3′R)‐2‐(2′,3′‐dicarboxy‐ cyclopropyl)glycine ([ 3 H]‐DCG IV) binding to metabotropic mGlu 2 receptor‐transfected cell membranes
Author(s) -
Cartmell Jayne,
Adam Geo,
Chaboz Sylvie,
Henningsen Robert,
Kemp John A.,
Klingelschmidt Agnes,
Metzler Veit,
Monsma Frederick,
Schaffhauser Hervé,
Wichmann Jürgen,
Mutel Vincent
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701647
Subject(s) - chemistry , kainate receptor , stereochemistry , agonist , ampa receptor , metabotropic receptor , metabotropic glutamate receptor 2 , metabotropic glutamate receptor , receptor , glutamate receptor , biochemistry
The binding of the new selective group II metabotropic glutamate receptor radioligand, [ 3 H]‐(2 S ,2′ R ,3′ R )‐2‐(2′,3′‐dicarboxycyclopropyl)glycine ([ 3 H]‐DCG IV), was characterized in rat mGlu 2 receptor‐transfected CHO cell membranes. [ 3 H]‐DCG IV binding was pH‐dependent, but was not sensitive to temperature. Saturation analysis showed the presence of a single binding site, with a K d value of 160 n M and a B max value of 10 pmol mg −1 protein. Binding was not sensitive to Na + ‐dependent glutamate uptake blockers or Cl − ‐dependent glutamate binding inhibitors. Furthermore, up to concentrations of 1 m M , the glutamate ionotropic receptor agonists, N‐methyl‐ D ‐aspartic acid (NMDA), ( S )‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) and kainate, did not affect [ 3 H]‐DCG IV binding. Of the compounds observed to inhibit [ 3 H]‐DCG IV binding, the most potent were the recently described selective group II agonist, (+)‐2‐aminobicyclo‐[3.1.0]hexane‐2,6‐dicarboxylate (LY 354740; K i value 16 n M ) and antagonist, 2‐amino‐2‐(2‐carboxycyclopropan‐1‐yl)‐3‐(dibenzopyran‐4‐yl) propanoic acid (LY 341495; K i value 19 n M ). As expected, for a G‐protein‐coupled receptor, guanosine‐5′‐O‐(3‐thiotriphosphate) (GTPγS) inhibited [ 3 H]‐DCG IV binding in a concentration‐dependent manner, with an IC 50 value of 12 n M . A highly significant correlation was observed between the potencies of compounds able to inhibit [ 3 H]‐DCG IV binding and potencies obtained for agonist activity in a GTPγ 35 S binding functional assay. In addition, these studies identified a number of compounds with previously unknown activity at mGlu 2 receptors, including L (+)‐2‐amino‐3‐phosphonopropionic acid ( L ‐AP3), L (+)‐2‐amino‐5‐phosphonopentanoic acid ( L ‐AP5), 3‐(( RS )‐2‐carboxypiperazin‐4‐yl)‐propyl‐1‐phosphonic acid ( R ‐CPP), N‐acetyl‐ L ‐aspartyl‐ L ‐glutamic acid (NAAG) and ( RS )‐α‐methylserine‐O‐phosphate (MSOP).British Journal of Pharmacology (1998) 123 , 497–504; doi: 10.1038/sj.bjp.0701647