title: Neuroprotective actions in vivo and electrophysiological actions in vitro of 202W92.
abstract: 202W92 (R-(-)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidine) is a novel compound in the same chemical series as the antiepileptic drug lamotrigine and the neuroprotective sipatrigine. Here 202W92 was quantitatively assessed as a neuroprotective agent in focal cerebral ischaemia, and as an inhibitor of sodium and calcium channels and of synaptic transmission. In the rat permanent middle cerebral artery occlusion (MCAO) model of acute focal ischaemia, 202W92 reduced infarct volume by 75% in cortex and by 80% in basal ganglia, with ED(50) 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 (IC(50) 3 x 10(-6) M) in rat freshly-isolated cortical neurons and in the GH(3) pituitary cell line. 202W92 also inhibited a nifedipine-sensitive fraction (approximately 35%) of native high-voltage-activated (HVA) calcium current in rat cortical neurons (IC(50) 15 x 10(-6) M) and weakly inhibited low-voltage-activated (LVA) calcium currents of the recombinant alpha1I-mediated T-type (IC(50)>100 x 10(-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 administered post-ischaemia and a potent sodium channel inhibitor in vitro.
authors.affiliation: Fondazione IRCCS Santa Lucia, 00179 Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Caputi
authors.forename: A H
authors.initials: AH
authors.lastname: Hainsworth
authors.forename: F
authors.initials: F
authors.lastname: Lavaroni
authors.forename: M J
authors.initials: MJ
authors.lastname: Leach
authors.forename: N C
authors.initials: NC
authors.lastname: McNaughton
authors.forename: N B
authors.initials: NB
authors.lastname: Mercuri
authors.forename: A D
authors.initials: AD
authors.lastname: Randall
authors.forename: F
authors.initials: F
authors.lastname: Spadoni
authors.forename: J H
authors.initials: JH
authors.lastname: Swan
authors.forename: A
authors.initials: A
authors.lastname: Stefani
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013687:Telencephalon / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
chemical_list: C443646:2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidine; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018696:Neuroprotective Agents; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D018698:Glutamic Acid