HMN-1180, a small molecule inhibitor of neuronal nitric oxide synthase.

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 microM. 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 microM). 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 the L-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.

• Authors: M Nishio, Y Watanabe, H Hidaka
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 287 Issue 3 Pg. 1063-7 (Dec 1998) ISSN: 0022-3565 [Print] United States
• PMID: 9864293 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Nitric Oxide
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• NOS1 protein, human
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type I
• Nos1 protein, rat
• HMN 1180
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, chemistry, pharmacology)
• Animals
• Brain (enzymology)
• Chromatography, Affinity
• Enzyme Inhibitors (pharmacology)
• Humans
• Nitric Oxide (analysis)
• Nitric Oxide Synthase (antagonists & inhibitors, chemistry, genetics)
• Nitric Oxide Synthase Type I
• Plasmids
• Rats
• Structure-Activity Relationship
• Tumor Cells, Cultured