FLUPIRTINE, A NONOPIOID CENTRALLY ACTING ANALGESIC, ACTS AS AN NMDA ANTAGONIST

1. Flupirtine (Katadolon) is a member of a class of triaminopyridines and is used as a nonopioid analgesic agent with muscle relaxant proper ties. 2. In situ experiments have revealed that flupirtine protects ag ainst ischemic-induced insults to the retina and brain. 3. Data derive d from in vitro and in vivo studies suggest that flupirtine functions as a weak N-methyl-D-aspartate (NMDA) antagonist with little evidence that it acts on AMPA-kainate type glutamate receptors. 4. No evidence could be found from binding studies to suggest that flupirtine has an affinity for any of the characterized binding sites associated with th e NMDA receptor. 5. Studies on cultured cortical neurons show that the NMDA-induced influx of Ca-45(2+) is more readily decreased by flupirt ine when a reducing agent (dithiothreitol) is present. However, when N '-ethylmaleimide, which is thought to alkylate the NMDA receptor redox site, is present, no obvious effect on the NMDA induced influx of Ca- 45(2+) is produced by flupirtine. 6. Flupirtine is also known to count eract the production of reactive oxygen species caused by ascorbate/ir on as well as to prevent apoptosis in cells lacking NMDA receptors ind uced by oxidative stress. 7. To explain all the experimental data, it is suggested that flupirtine affects the redox state/pH/electrons in t he cell. The specific way by which flupirtine antagonizes the NMDA rec eptor might be by an action on the known redox site of the receptor. ( C) 1998 Elsevier Science Inc.