Inhibition of nitric oxide synthase with pyrazole-1-carboxamidine and related compounds

Garry J. Southan, Douglas Gauld, Andrew Lubeskie, Basilia Zingarelli, Salvatore Cuzzocrea, Andrew L. Salzman, Csaba Szabo, Donald J. Wolff

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Guanidines, amidines, S-alkylisothioureas, and other compounds containing the amidine function (-C(=NH)NH2) have been described as inhibitors of the generation of nitric oxide (NO) by NO synthase (NOS). Mere we report on the inhibition of the activity of NOS isoforms by compounds in which the amidine function is attached to a nitrogen of 1,2 diazo heterocycles to form N-carboxamidines and related compounds. 1H-Pyrazole-1-carboxamidine HCl (PCA) inhibited the activity of purified inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS) isoforms to a similar extent (IC50 = 0.2 μM). 3-Methyl-PCA and 4-methyl-PCA showed reduced potencies, but a preference for iNOS [IC50 = 5 and 2.4 μM, respectively; cf. N(G)-methyl-L-arginine (NMA) IC50 = 6 μM]. Inhibition of purified iNOS by PCAs could be reversed completely by excess L arginine, while their inhibition of NO production by stimulated RAW macrophages could be reversed by transfer to a drug-free medium. This suggests a competitive mode of inhibition. PCA caused potent concentration dependent inhibition of the acetylcholine-induced, endothelium-dependene relaxations of precontracted rat thoracic aorta (IC50 = 30 μM). 4-Methyl-PCA inhibited the relaxations only at ≤300 μM. In contrast, 4-methyl-PCA was more effective than both PCA and NMA in restoring the ex vivo contractility of aortic rings taken from lipopolysaccharide-treated rats. PCA and NMA, but not 4-methyl-PCA, caused marked increases in mean arterial pressure when administered i.v. to anesthetized rats. In conclusion, PCA and related compounds caused potent inhibition of NOS. Substitution of the pyrazole ring reduced potency, but improved selectivity towards iNOS as exemplified by 4-methyl-PCA.

Original languageEnglish (US)
Pages (from-to)409-417
Number of pages9
JournalBiochemical Pharmacology
Volume54
Issue number3
DOIs
StatePublished - Aug 1 1997
Externally publishedYes

Fingerprint

Nitric Oxide Synthase
Amidines
Inhibitory Concentration 50
Rats
Arginine
Nitric Oxide
Protein Isoforms
pyrazole-1-carboxamidine
Guanidines
Passive Cutaneous Anaphylaxis
Macrophages
Thoracic Aorta
Acetylcholine
Endothelium
Lipopolysaccharides
Arterial Pressure
Substitution reactions
Nitrogen

Keywords

  • Blood pressure
  • Inhibition
  • L-arginine
  • Nitric oxide sythase
  • Pyrazole-1-carboxamidine

ASJC Scopus subject areas

  • Pharmacology

Cite this

Southan, G. J., Gauld, D., Lubeskie, A., Zingarelli, B., Cuzzocrea, S., Salzman, A. L., ... Wolff, D. J. (1997). Inhibition of nitric oxide synthase with pyrazole-1-carboxamidine and related compounds. Biochemical Pharmacology, 54(3), 409-417. https://doi.org/10.1016/S0006-2952(97)00196-2

Inhibition of nitric oxide synthase with pyrazole-1-carboxamidine and related compounds. / Southan, Garry J.; Gauld, Douglas; Lubeskie, Andrew; Zingarelli, Basilia; Cuzzocrea, Salvatore; Salzman, Andrew L.; Szabo, Csaba; Wolff, Donald J.

In: Biochemical Pharmacology, Vol. 54, No. 3, 01.08.1997, p. 409-417.

Research output: Contribution to journalArticle

Southan, GJ, Gauld, D, Lubeskie, A, Zingarelli, B, Cuzzocrea, S, Salzman, AL, Szabo, C & Wolff, DJ 1997, 'Inhibition of nitric oxide synthase with pyrazole-1-carboxamidine and related compounds', Biochemical Pharmacology, vol. 54, no. 3, pp. 409-417. https://doi.org/10.1016/S0006-2952(97)00196-2
Southan GJ, Gauld D, Lubeskie A, Zingarelli B, Cuzzocrea S, Salzman AL et al. Inhibition of nitric oxide synthase with pyrazole-1-carboxamidine and related compounds. Biochemical Pharmacology. 1997 Aug 1;54(3):409-417. https://doi.org/10.1016/S0006-2952(97)00196-2
Southan, Garry J. ; Gauld, Douglas ; Lubeskie, Andrew ; Zingarelli, Basilia ; Cuzzocrea, Salvatore ; Salzman, Andrew L. ; Szabo, Csaba ; Wolff, Donald J. / Inhibition of nitric oxide synthase with pyrazole-1-carboxamidine and related compounds. In: Biochemical Pharmacology. 1997 ; Vol. 54, No. 3. pp. 409-417.
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