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Research ArticleArticle

HMN-1180, a Small Molecule Inhibitor of Neuronal Nitric Oxide Synthase

Masahiro Nishio, Yasuo Watanabe and Hiroyoshi Hidaka
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 1063-1067;
Masahiro Nishio
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Yasuo Watanabe
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Hiroyoshi Hidaka
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Abstract

A newly synthesized isoquinolinesulfonamide, HMN-1180 (1-(5-isoquinolinylsulfonyl)-7-methylhomopiperazine), was shown to have selective inhibitory action against rat neuronal nitric oxide synthase (nNOS) with a Ki value of 5.4 μM. Kinetic analysis indicated that the inhibition was competitive with respect to l-arginine but not to calmodulin (CaM). However HMN-1180 exhibited no significant influence up to a concentration of 1 mM on activity of endothelial NOS (eNOS) and it was less active toward inducible NOS (iNOS) (IC50 > 100 μM). Moreover, nNOS bound to a HMN-1180-coupled Sepharose column, but eNOS and iNOS did not. These results suggest that inhibition of nNOS activity is due to direct binding of the compound to thel-arginine binding site of the synthase. Several HMN-1180 derivatives were synthesized and analyzed for their inhibitory actions against nNOS, eNOS and iNOS to cast light on its structure-activity relationships. The potency of inhibition proved dependent on the position of methyl group in the homopiperazine molecule. HMN-1180 was also found to inhibit glutamate stimulated NO production generated by nNOS in the human neuroblastoma cell line SK-N-MC, thus indicating that it is useful tool for elucidating the physiological role of nNOS in neuronal function.

Footnotes

  • Send reprint requests to: Dr. Hiroyoshi Hidaka, Department of Pharmacology, Nagoya University School of Medicine, Showa-ku, Nagoya 466-8550,Japan. E-mail: hhidaka{at}tsuru.med.nagoya-u.ac.jp

  • ↵1 This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas (to H.H.) and a Grant-in-Aid for Scientific Research (to Y.W.) from the Ministry of Education, Science, Sports and Culture.

  • Abbreviations:
    NOS
    nitric oxide synthase
    CaM
    calmodulin
    PKA
    cAMP-dependent protein kinase
    CaMKII
    Ca++/CaM-dependent protein kinase II
    NADPH
    β-nicotinamide dinucleotide phosphate
    BH4
    (6R)-5, 6, 7, 8- tetrahydro-l-biopterin
    SDS-PAGE
    sodium dodecyl sulfate-polyacrylamide gel electrophoresis
    l-NAME
    N-nitro-l-arginine methyl ester
    PBS
    phosphate-buffered saline
    MEM
    minimum essential medium
    PVDF
    polyvinylidene difluoride
    CREB
    cyclic AMP response element binding protein
    • Received April 21, 1998.
    • Accepted July 8, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

HMN-1180, a Small Molecule Inhibitor of Neuronal Nitric Oxide Synthase

Masahiro Nishio, Yasuo Watanabe and Hiroyoshi Hidaka
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 1063-1067;

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Research ArticleArticle

HMN-1180, a Small Molecule Inhibitor of Neuronal Nitric Oxide Synthase

Masahiro Nishio, Yasuo Watanabe and Hiroyoshi Hidaka
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 1063-1067;
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