NEUROPROTECTANT EFFECTS OF LY-274614, A STRUCTURALLY NOVEL SYSTEMICALLY ACTIVE COMPETITIVE NMDA RECEPTOR ANTAGONIST

Antagonists for the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor may have therapeutic potential as neuroprotectant agents in conditions of neuronal degeneration that include brain ischemia, Huntington's chorea, and Alzheimer's disease. Here we have investigated the pharmacological actions of LY 274614, a structurally novel competitive NMDA receptor antagonist, for pharmacological selectivity and neuroprotectant effects following systemic administration. LY 274614 potently displaced NMDA receptor ([H-3]CGS19755) binding (IC50 = 58.8 +/- 10.3 nM), but had no appreciable affinity at [H-3]AMPA or [H-3]kainate receptor sites at up to 10,000 nM. NMDA-induced convulsions in neonatal rats or NMDA-induced lethality in mice are potently and selectively antagonized by i.p. or p.o. LY 274614. Oral doses showed a delayed but prolonged duration of effect. In adult rats, the neurodegenerative effects (loss of choline acetyltransferase activity) following the intrastriatal infusions of NMDA or quinolinate, but not kainate, were prevented by LY 274614 (2.5 to 20 mg/kg i.p.). LY 274614 is an effective neuroprotectant agent against NMDA receptor-induced toxicity when administered systemically and is a promising therapeutic agent for conditions where glutamate plays a role in the pathology of neuronal degeneration.