Stereoselective neuroprotection by novel 2,3-benzodiazepine noncompetitiveAMPA antagonists against non-NMDA receptor-mediated excitotoxicity in primary rat hippocampal cultures

Glutamate excitotoxicity has been implicated in a variety of acute and chro nic neurodegenerative diseases but early phase clinical trials with competi tive antagonists at both N-methyl-D-aspartate (NMDA)-receptors and alpha-am ino-3-hydroxy-5-methylisoxazotepropionate (AMPA) receptors have been disapp ointing. A family of atypical 2,3 benzodiazepines, exemplified by GYK1 5246 6, have been described recently which function as non-competitive AMPA-rece ptor antagonists. We have investigated the neuroprotective efficacy of LY30 3070 and LY300164, two analogs of GYKI-52466, in an embryonic rat hippocamp al culture model of non-NMDA receptor-mediated excitotoxicity using kainic acid (KA) as an agonist at the AMPA/KA receptor. Overnight treatment with 5 00 mu M KA resulted in prominent neuronal excitotoxicity as assessed by lac tate dehydrogenase efflux. LY300164 and LY303070 attenuated KA-excitotoxici ty in a dose-dependent manner with IC(50)s Of 4 and 2 mu M, respectively. I n contrast, their stereoisomers, LY300165 and LY303071 showed no neuroprote ction at concentrations up to 25 mu M. In addition, AMPA-mediated excitotox icity in cyclothiazide pre-treated cultures was also completely blocked by LY303070. Finally, neuroprotection by this class of 2,3 benzodiazepines was not influenced by antagonism of the classical benzodiazepine receptor. LY3 03070 and LY300164 represent novel non-competitive AMPA-receptor antagonist s which may offer unique advantages in the clinic over competitive AMPA-rec eptor antagonists. (C) 1999 Elsevier Science Ireland Ltd. All rights reserv ed.