Inhibition of neuronal nitric oxide synthase activity by 3-[2-[4-(3-chloro-2-methylphenyl)- 1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel neuroprotective agent, in vitro and in cultured neuroblastoma cells in situ

Kohji Fukunaga, Masao Ohmitsu, Eishichi Miyamoto, Toshiyuki Sato, Masunobu Sugimura, Toshihiro Uchida, Yasufumi Shirasaki

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

DY-9760e, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, a novel calmodulin (CaM) antagonist, possesses neuroprotective activity. In the current study, we examined the effects of DY-9760e on nitric oxide synthase (NOS) activities in vitro and on calcium ionophore-induced NO production in situ. DY-9760e inhibited both neuronal NOS and endothelial NOS activities without affecting inducible NOS activity. It also inhibited purified neuronal NOS activity with a potency similar to that seen for purified CaM kinase II activity in vitro. Furthermore, DY-9760e significantly inhibited Ca2+ ionophore (A23187)-induced NO production in mouse N1E-115 neuroblastoma cells, at a concentration of less than 1 μM. In contrast, no apparent inhibitory effect on Ca2+/CaM-dependent protein kinase II activity was observed in cultured hippocampal neurons up to 5 μM. These results suggest that the inhibitory effect of DY-9760e on CaM-dependent NOS activities underlies neuroprotective effects of the agent. Copyright (C) 2000 Elsevier Science Inc.

Original languageEnglish
Pages (from-to)693-699
Number of pages7
JournalBiochemical Pharmacology
Volume60
Issue number5
DOIs
Publication statusPublished - 2000 Sep 1
Externally publishedYes

Keywords

  • Brain ischemia
  • CaM kinase II
  • Calmodulin antagonist
  • Neuroprotection
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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