Paul Ornstein - (3H)-LY341495 as a novel antagonist radioligand for group II metabotropic glutamate (mGlu) receptors: Characterization of binding to membranes of mGlu receptor subtype expressing cells

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  Johnson, Bryan G., Wright, Rebecca A., Arnold, M. Brian, Wheeler,   William J., Ornstein, Paul L., Schoepp, Darryle D.   Neuropharmacology 1999 38 (10)   1519-1529

  Abstract: Metabotropic glutamate (mGlu)   receptors are a family of eight known subtypes termed mGlu1-8.   Currently, few ligands are available to study the pharmacology of   mGlu receptor subtypes. In functional assays, we previously   described LY341495 as a highly potent and selective mGlu2 and   mGlu3 receptor antagonist. In this study, radiolabeled   (3H)-LY341495 was used to investigate the characteristics of   receptor binding to membranes from cells expressing human mGlu   receptor subtypes. Using membranes from cells expressing human   mGlu2 and mGlu3 receptors, (3H)-LY341495 (1 nM) specific binding   was > 90% of total binding. At an approximate KD concentration   for (3H)-LY341495 binding to human mGlu2 and mGlu3 receptors (1   nM), no appreciable specific binding of (3H-)LY341495 was found   in membranes of cells expressing human mGlu1a, mGlu5a, mGlu4a,   mGlu6, or mGlu7a receptors. However, modest (apprx 20% of   mGlu2/3) specific (3H)-LY341495 (1 nM) binding was observed in   human mGlu8 expressingcells. (3H)-LY341495 bound to membranes   expressing human mGlu2 and mGlu3 receptors in a reversible and   saturable manner with relatively high affinities (Bmax 20.5 +-   5.4 and 32.0 +- 7.0 pmol/mg protein; and KD = 1.67 +- 0.20 and   0.75 +- 0.43 nM, respectively). The pharmacology of (3H)-LY341495   binding in mGlu2 and mGlu3 expressing cells was consistent with   that previously described for LY341495 in functional assays.   (3H)-LY341495 binding provides a useful way to further   investigate regulation of receptor expression and pharmacological   properties of mGlu2 and mGlu3 receptor subtypes in recombinant   systems.

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