title: Neuroprotectant effects of LY274614, a structurally novel systemically active competitive NMDA receptor antagonist.
abstract: 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 LY274614, a structurally novel competitive NMDA receptor antagonist, for pharmacological selectivity and neuroprotectant effects following systemic administration. LY274614 potently displaced NMDA receptor ([3H]CGS19755) binding (IC50 = 58.8 +/- 10.3 nM), but had no appreciable affinity at [3H]AMPA or [3H]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. LY274614. 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 LY274614 (2.5 to 20 mg/kg i.p.). LY274614 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.
authors.affiliation: Central Nervous System Research, Eli Lilly and Company, Indianapolis, IN.
authors.forename: D D
authors.initials: DD
authors.lastname: Schoepp
authors.forename: P L
authors.initials: PL
authors.lastname: Ornstein
authors.forename: C R
authors.initials: CR
authors.lastname: Salhoff
authors.forename: J D
authors.initials: JD
authors.lastname: Leander
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D001667:Binding, Competitive; D001921:Brain / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D007546:Isoquinolines; D007608:Kainic Acid / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D009410:Nerve Degeneration / Q000187:drug effects*; D016318:Quisqualic Acid / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
chemical_list: D000927:Anticonvulsants; D007546:Isoquinolines; D016194:Receptors, N-Methyl-D-Aspartate; C070935:LY 274614; D007051:Ibotenic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D016318:Quisqualic Acid; D007608:Kainic Acid