Neuropharmacology 37 (1998) 1211 – 1222 Decahydroisoquinolines: novel competitive AMPA/kainate antagonists with neuroprotective effects in global cerebral ischaemia Michael J. O’Neill a, *, Ann Bond a , Paul L. Ornstein b , Mark A. Ward a , Caroline A. Hicks a , Ken Hoo c , David Bleakman b , David Lodge b a Lilly Research Centre, Eli Lilly and Co. Ltd., Erl Wood Manor, Windlesham GU20 6PH, UK b Lilly Corporate Center, Indianapolis, IN 46285 -0814, USA c Allelix Biopharmaceuticals Inc., 6850 Goreway Drie, Mississauga, Ont. L4V1V7, Canada Accepted 5 August 1998 Abstract In the present studies, we have evaluated the activity of a series of glutamate receptor antagonists from the decahydroisoquino- line group of compounds both in vitro and in vivo. Compound activity at  -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. © 1998 Elsevier Science Ltd. All rights reserved. Keywords: AMPA antagonist; Cerebral ischemia; Gerbil; iGluR5; LY293558; LY377770; Neuroprotection 1. Introduction Glutamate is the major excitatory neurotransmitter in the central nervous system (Collingridge and Lester, 1989). Glutamate activates ligand gated ion channels (ionotropic glutamate receptors or iGluRs) and recep- tors coupled to second messenger systems (metabo- tropic glutamate receptors or mGluRs). The ionotropic receptors are divided into two distinct subtypes, namely, the N -methyl-D-aspartate (NMDA) receptor and  -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptor subtypes (Watkins and Olverman, 1987). The excessive increase of extracellular glutamate fol- lowing ischaemia is thought to play a critical role in the development of neuronal damage (Choi et al., 1987, 1988, Globus et al., 1988, Butcher et al., 1990). Several studies have indicated that many compounds acting as excitatory amino acid receptor antagonists have benefi- cial effects against cerebral ischaemia (Gill et al., 1987, Grotta et al., 1990, Sheardown et al., 1990, Bullock et al., 1994). Many of the early studies demonstrated that non-competitive and competitive NMDA receptor an- tagonists (Boast et al., 1988, Gotti et al., 1990, Grotta et al., 1990, Park et al., 1992) were neuroprotective following global and focal cerebral ischaemia. How- ever, NMDA antagonists have side-effect issues includ- ing psychotomimetic activity (Koek et al., 1988). More recently, studies have shown the neuroprotec- tive actions of competitive AMPA receptor antagonists in animal models of cerebral ischaemia (Bullock et al., * Corresponding author. Tel.: +44 1276 853547; fax: +44 1276 853525; e-mail: ONEILL – MICHAEL – J@Lilly.com. 0028-3908/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PII: S00 2 8 - 3908(98)00 1 3 4- 8