Neuroprotective actions in vivo and electrophysiological actions in vitro of 202W92

202W92 (R-(-)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidi ne) is a novel compound in the same chemical series as the antiepileptic dr ug lamotrigine and the neuroprotective sipatrigine. Here 202W92 was quantit atively assessed as a neuroprotective agent in focal cerebral ischaemia, an d as an inhibitor of sodium and calcium channels and of synaptic transmissi on. In the rat permanent middle cerebral artery occlusion (MCAO) model of a cute focal ischaemia, 202W92 reduced infarct. volume by 75% in cortex and b y 80% in basal ganglia, with ED50 approximately 2 mg/kg (single i.v. dose, 10 min post-occlusion). In whole-cell current recordings from single cells, 202W92 completely and reversibly inhibited voltage gated sodium channels ( IC50 3x10(-6) M) in rat freshly-isolated cortical neurons and in the GH, pi tuitary cell line. 202W92 also inhibited a nifedipine-sensitive fraction (a pproximately 35%) of native high-voltage-activated (HVA) calcium current in rat cortical neurons (IC50 15x10(-6) M) and weakly inhibited low-voltage-a ctivated (LVA) calcium currents of the recombinant alpha 1I-mediated T-type (IC50> 100x10(-6) M). The drug inhibited the amplitude and frequency of 4- aminopyridine-evoked glutamatergic excitatory post-synaptic currents (EPSCs ). In conclusion, 202W92 is an effective neuroprotective agent when adminis tered post-ischaemia and a potent sodium channel inhibitor in vitro. (C) 20 01 Elsevier Science B.V. All rights reserved.