title: Blockade of voltage-sensitive sodium channels by NS-7, a novel neuroprotective compound, in the rat brain.
abstract: The effects of 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7), a novel neuroprotective compound, on the voltage-sensitive sodium channels (VSSC) were examined in the rat brain and cardiac myocytes. NS-7 inhibited [3H]batrachotoxinin A 20 alpha-benzoate (BTX) binding (neurotoxin receptor site 2) in brain membranes with a Ki value of 1 microM, while the compound was less effective in the cardiac myocytes (Ki = 13 microM). Aconitine, on the other hand, inhibited [3H]BTX binding to brain membranes and cardiac myocytes with the same potency. In contrast. NS-7 had no affinity for [3H]saxitoxin binding in brain (neurotoxin receptor site 1). In superfused slices of the rat cerebral cortex, NS-7 inhibited the veratridine (5 microM)-evoked glutamate release in a concentration-dependent manner, the IC50 value of which was 7.7 microM, whereas the compound showed a weak and not significant suppression of KCl-evoked glutamate release. The tissue concentrations of NS-7 in the rat cerebral cortex and heart were 89 and 28 nmole/g tissue, respectively, 5 min after its intravenous injection (8 mg/kg). Furthermore, in the cerebral cortex, NS-7 distributed preferentially to the membrane-enriched synaptosomal fraction. Since neurotoxin receptor site 2 is located in the transmembrane region of the VSSC moiety, the channel function may be substantially inhibited by a peripheral administration of NS-7. These results suggest that the blockade of neurotoxin receptor site 2 of VSSC in the brain contributes to the neuroprotective action of NS-7.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shimidzu
authors.forename: Y
authors.initials: Y
authors.lastname: Itoh
authors.forename: S
authors.initials: S
authors.lastname: Tatsumi
authors.forename: S
authors.initials: S
authors.lastname: Hayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Ukai
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshikuni
authors.forename: K
authors.initials: K
authors.lastname: Kimura
mesh_terms: D000157:Aconitine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001496:Batrachotoxins / Q000378:metabolism; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009498:Neurotoxins / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012530:Saxitoxin / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology
chemical_list: C106144:4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride; D001496:Batrachotoxins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011743:Pyrimidines; D015222:Sodium Channels; D012530:Saxitoxin; D018698:Glutamic Acid; D011189:Potassium Chloride; D014701:Veratridine; C031775:batrachotoxinin A 20-alpha-benzoate; D000157:Aconitine