DECAHYDROISOQUINOLINES - NOVEL COMPETITIVE AMPA KAINATE ANTAGONISTS WITH NEUROPROTECTIVE EFFECTS IN GLOBAL CEREBRAL-ISCHEMIA/

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 lpha-amino- 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate recept ors was assessed using ligand binding to cloned iGluR2 and iGluR5 rece ptors and on responses evoked by AMPA and N-methyl-D-aspartate (NMDA) in the cortical wedge preparation. In vivo, compounds were examined fo r antagonist activity electrophysiologically in the rat spinal cord pr eparation and in the gerbil model of global cerebral ischaemia. Compou nds 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, LY2 80263, LY289178, LY289525, LY294486 (AMPA/kainate antagonists) and LY3 82884 (an iGluR5 selective antagonist). Results obtained support a rol e for AMPA receptors in cerebral ischemia. LY377770 (a mixed AMPA/iGlu R5 antagonist and active isomer of LY294486) demonstrated good neuropr otection with a 2-h time window and may therefore be useful in the tre atment of ischaemic conditions. (C) 1998 Elsevier Science Ltd. All rig hts reserved.