Paul Ornstein - Decahydroisoquinolines: Novel competitive AMPA/kainate antagonists with neuroprotective effects in global cerebral ischaemia

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  O'Neill, Michael J., Bond, Ann, Ornstein, Paul L., Ward, Mark A.,   Hicks, Caroline A., Hoo, Ken, Bleakman, David, Lodge, David   Neuropharmacology 1998 37  (10-11) 1211-1222

  Abstract: In the present studies, we have   evaluated the activity of a series of glutamate receptor   antagonists from the decahydroisoquinoline group of compounds   both in vitro and in vivo. Compound activity at   alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)   and kainate receptors was assessed using ligand binding to cloned   iGluR2 and iGluR5 receptors and on responses evoked by AMPA and   N-methyl-D-aspartate (NMDA) in the cortical wedge preparation. In   vivo, compounds were examined for antagonist activity   electrophysiologically in the rat spinal cord preparation and in   the gerbil model of global cerebral ischaemia. Compounds tested   were LY293558, which has been shown to protect in models of focal   cerebral ischaemia, LY202157 (an NMDA antagonist), LY246492 (an   NMDA and AMPA receptor antagonist), LY302679, LY292025, LY307190,   LY280263, LY289178, LY289525, LY294486 (AMPA/kainate antagonists)   and LY382884 (an iGluR5 selective antagonist). Results obtained   support a role for AMPA receptors in cerebral ischemia. LY377770   (a mixed AMPA/iGluR5 antagonist and active isomer of LY294486)   demonstrated good neuroprotection with a 2-h time window and may   therefore be useful in the treatment of ischaemic conditions.

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