Decahydroisoquinolines: novel competitive AMPA/kainate antagonists with neuroprotective effects in global cerebral ischaemia.
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.
O'Neill
M J
MJ
Lilly Research Centre, Eli Lilly and Co. Ltd., Windlesham, UK. ONEILL_MICHAEL_J@Lilly.com
Bond
A
A
Ornstein
P L
PL
Ward
M A
MA
Hicks
C A
CA
Hoo
K
K
Bleakman
D
D
Lodge
D
D
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005849:Gerbillinae; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors