Paul Ornstein - Binding of (3H)(2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycyclopropyl) glycine ((3H)LY341495) to cell membranes expressing recombinant human group III metabotropic glutamate receptor subtypes

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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. Naunyn-Schmiedeberg's   Archives of Pharmacology 2000 362  (6) 546-554

      Abstract: LY341495 is a highly potent and   selective antagonist for group II mGlu receptors (mGlu2 and   mGlu3). High affinity binding of (3H)LY341495 to recombinant   human group II mGlu receptors (mGlu2 and mGlu3), and in rat brain   homogenates (Kd apprx1 nM), has been previously described.   Although LY341495 is a very selective nM-potent antagonist for   group II mGlu receptors, it is also a relatively potent   antagonist for group III mGlu receptors at high nanomolar to low   micromolar concentrations. In this study we examined and   characterized the binding of (3H)LY341495 to membranes of cells   expressing recombinant human group III mGlu receptors. Using up   to 100 nM of (3H)LY341495, the level of specific binding in human   mGlu4a receptor-expressing cell membranes was not appreciable and   binding to this site was not examined further. In contrast, we   demonstrated sufficient specific binding of (3H)LY341495 to human   mGlu6, mGlu7a and mGlu8a receptor-expressing cell membranes to   allow for further characterizations. (3H)LY341495 binding was   saturable and rapidly reversible. (3H)LY341495 bound to a single   site in each cell line, with Kd and Bmax values of 31.6+-6.8 nM   and 3.3+-0.7 pmol/mg protein (mGlu6), 72.7+-22.0 nM and 3.7+-0.4   pmol/mg protein (mGlu7a), and 14.0+-1.1 nM and 3.0+-0.2 pmol/mg   protein (mGlu8a). (3H)LY341495 binding to mGlu6, 7a and 8a was   displaceable by compounds which interact functionally with group   III mGlu receptors. For example, L-AP4 displaced (3H)LY341495   with Ki values of 6.8+-3.1 muM (mGlu6), 211+-43 muM (mGlu7a) and   1.6+-0.3 muM (mGlu8a). With L-glutamate, we obtained Ki values of   12.3+-3.5, 869+-154 and 4.5+-0.83 muM, for mGlu6, mGlu7a and   mGlu8a, respectively. Ki values for unlabelled LY341495 were   0.058+-0.008, 0.22+-0.05 and 0.029+-0.008 muM, respectively.   These studies demonstrated that (3H)LY341495 is a useful   radioligand for studying the pharmacology and expression of   recombinant mGlu6, 7a and 8a receptors in cell lines.

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