Paul Ornstein - (3H)LY341495 binding to group II metabotropic glutamate receptors in rat brain

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  Publication Details (including relevant citation   information):

  Wright, Rebecca A., Arnold, M. Brian, Wheeler, William J.,   Ornstein, Paul L., Schoepp, Darryle D. Journal of   Pharmacology and Experimental Therapeutics  2001 298 (2) 453-460

  Abstract: (3H)LY341495 is a highly potent and   selective antagonist for group II metabotropic glutamate (mGlu)   receptors (mGlu2 and mGlu3), which has been used to label these   receptors in cells expressing recombinant receptor subtypes. In   this study, we characterized the kinetics, pharmacology, and   distribution of (3H)LY341495 binding to mGlu receptors in rat   brain tissue. Equilibrium experiments in the rat forebrain   demonstrated binding to a single site that was saturable,   reversible, and of high affinity (Bmax, 3.9+-0.65 pmol/mg of   protein, Kd, 0.84+-0.11 nM). The relative order of potencies for   displacement of (3H)LY341495 by mGlu receptor ligands was   LY341495 mchgt L-glutamic   acid>LY354740>(2S,1'S,2'S)-2-(carboxycyclopropyl)glycine>4-(2R,4R)-aminopyrroli dine-2,4-dicarboxylate>(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic   acid>(R,S)-alpha-methyl-4-phosphonophenylglycine>(R,S)3,5-dihydroxyphenylglycin e>L-(+)-2-amino-4-phosphonobutyric   acid. (3H)LY341495 was not displaced by the selective ionotropic   glutamate receptor agonists N-methyl-D-aspartic acid,   (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid,   or kainate at concentrations up to 1 mM. Comparison of   (3H)LY341495 binding in rat brain with recombinant mGlu receptor   subtypes demonstrated a very high correlation with mGlu3 receptor   binding (r2=0.957), a significant, but lower, correlation with   mGlu2 receptor binding (r2=0.869), but no significant correlation   to mGlu8 receptor binding (r2=0.284). Regional studies using   autoradiography showed a similar distribution of (3H)LY341495   binding to that for group II mGlu receptors previously reported   by others using immunocytochemical techniques. These studies   indicate that (3H)LY341495 selectively labels group II (mGlu2/3)   receptors, but under the conditions used, (3H)LY341495 may bind   predominately to mGlu3 receptor populations in the rat forebrain.

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