Activity of 2,3-benzodiazepines at Native Rat and Recombinant Human Glutamate Receptors In Vitro: Stereospecificity and Selectivity Profiles
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The activity and selectivity of the glutamate receptor antagonists belonging to the 2,3-benzodiazepine class of compounds have been examined at recombinant human non-NMDA glutamate receptors expressed in HEK293 cells and on native rat NMDA and non-NMDA receptors in vitro. The racemic 2,3-benzodiazepines GYK152466, LY293606 (GYKI53405) and LY300168 (GYKI53655) inhibited AMPA (10 μM)-mediated responses in recombinant human GluR1 receptors expressed in HEK293 cells with approximate ic50 values of 18 μM, 24 μM and 6 μM, respectively and AMPA (10 μM) responses in recombinant human GluR4 expressing HEK293 cells with approximate ic50 values of 22 μM, 28 μM and 5 μM, respectively. GYKI 52466, LY293606 and LY300168 were non-competitive antagonists of AMPA receptor-mediated responses in acutely isolated rat cerebellar Purkinje neurons with approximate ic50 values of 10 μM, 8 μM and 1.5 μM, respectively. The activity of racemic compounds LY293606 and LY300168 was established to reside in the (−) isomer of each compound. At a concentration of 100 μM, GYKI52466, LY293606 and LY300168 produced <30 % inhibition of kainate-activated currents evoked in HEK293 cells expressing either human homomeric GluR5 or GluR6 receptors or heteromeric GluR6+KA2 kainate receptors. The activity of the 2,3-benzodiazepines at 100 μM was weak at kainate receptors, but was stereoselective. Similar levels of inhibition were observed for kainate-induced currents in dorsal root ganglion neurons. Intact tissue preparations were also used to examine the stereoselective actions of the 2,3-benzodiazepines. In the cortical wedge preparation, the active isomer of LY300168, LY303070, produced a non-competitive antagonism of AMPA-evoked depolarizations with smaller changes in depolarizations induced by kainate and no effect on NMDA-dependent depolarizations. LY303070 was also effective in preventing 30 μM AMPA-induced depolarizations in isolated spinal cord dorsal roots with an approximate ic50 value of 1 μM. Synaptic transmission in the hemisected spinal cord preparation was stereoselectively antagonized by the active isomers of LY300168 and LY293606. In summary, these results indicate that 2,3-benzodiazepines are potent, selective and stereospecific antagonists of the AMPA subtype of the non-NMDA glutamate receptor. © 1997 Elsevier Science Ltd. All rights reserved. align=""top""> ace=""arial"" size=""-1"" color=""black""> Publisher: align=""top""> ace=""arial"" size=""-1"" color=""black""> Elsevier Science align=""top""> ace=""arial"" size=""-1"" color=""black""> Language of Publication: align=""top""> ace=""arial"" size=""-1"" color=""black""> English align=""top""> ace=""arial"" size=""-1"" color=""black""> Item Identifier: align=""top""> ace=""arial"" size=""-1"" color=""black""> S0028-3908(96)00156-6 align=""top""> ace=""arial"" size=""-1"" color=""black""> Publication Type: align=""top""> ace=""arial"" size=""-1"" color=""black""> Article align=""top""> ace=""arial"" size=""-1"" color=""black""> ISSN: align=""top""> ace=""arial"" size=""-1"" color=""black""> 0028-3908 align=""top""> ace=""arial"" size=""-1"" color=""black""> Cited by: align=""top""> ace=""arial"" size=""-1"" color=""black"">
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ace=""arial"" size=""-1"" color=""black""> Footnotes:
    <a name=""footnote_1"">

  1. The first two authors contributed equally to this work.

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