S-Substituted isothioureas are potent inhibitors of nitric oxide biosynthesis in cartilage

Daniel Jang, Csaba Szabo, George A C Murrell

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Nitric oxide (NO.) is a multifunctional messenger molecule generated by a family of enzymes, the nitric oxide synthases, and is overproduced in osteoarthritis and rheumatoid arthritis. Chondrocytes are the major native source of NO. in diarthrodial joints. Chondrocytic inducible nitric oxide synthase induced by inflammatory cytokines and bacterial cell wall fragments mediates many of the catabolic events in arthritis. Agents which specifically inhibit chondrocyte inducible NO. synthase, may thus have a role in the management in arthritis. We evaluated a novel class of potential inducible NO. synthase inhibitors, the S-substituted isothioureas, for their ability to inhibit inducible NO. synthase activity in cultured bovine chondrocytes and explants of cartilage from patients with osteoarthritis. Two isothioureas, S-methyl isothiourea and S-(aminoethyl) isothiourea were 2-4 times more potent than N(G)-monomethyl-L-arginine monoacetate, 5-10 times more potent than aminoguanidine and over 300 times more potent than N(ω)-nitro-L-arginine and N(ω)-nitro-L-arginine methyl ester. The rank order of potency of the NO. synthase inhibitors was S-(aminoethyl) isothiourea > S-methyl isothiourea > N(G)-monomethyl-L-arginine > aminoguanidine > N(ω)-nitro-L-arginine = N(ω)-nitro-L-arginine methyl ester. The order of potency was reversed (N(ω)-nitro-L-arginine methyl ester = N(ω)-nitro-L-arginine > N(G)-monomethyl-L-arginine = S-methyl isothiourea > S-(aminoethyl) isothiourea > aminoguanidine) when evaluating the same compounds ability to inhibit constitutive NO. synthase activity in bovine endothelial cells. In comparison to conventional arginine-based analogs, the isothioureas represent a more potent and relatively specific class of inhibitors of inducible NO. synthase in cartilage and thus may be beneficial in the management of arthritis.

Original languageEnglish (US)
Pages (from-to)341-347
Number of pages7
JournalEuropean Journal of Pharmacology
Volume312
Issue number3
DOIs
StatePublished - Oct 3 1996
Externally publishedYes

Fingerprint

Cartilage
Nitric Oxide
Arginine
Chondrocytes
Arthritis
Osteoarthritis
beta-Aminoethyl Isothiourea
Nitric Oxide Synthase Type II
Nitric Oxide Synthase
Cell Wall
Rheumatoid Arthritis
Endothelial Cells
Joints
Cytokines
Enzymes
pimagedine
arginine methyl ester
S-methylisothiopseudouronium

Keywords

  • Arthritis
  • Cartilage
  • Chondrocyte
  • Free radical
  • Inducible
  • Nitric oxide (NO) synthase

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

S-Substituted isothioureas are potent inhibitors of nitric oxide biosynthesis in cartilage. / Jang, Daniel; Szabo, Csaba; Murrell, George A C.

In: European Journal of Pharmacology, Vol. 312, No. 3, 03.10.1996, p. 341-347.

Research output: Contribution to journalArticle

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N2 - Nitric oxide (NO.) is a multifunctional messenger molecule generated by a family of enzymes, the nitric oxide synthases, and is overproduced in osteoarthritis and rheumatoid arthritis. Chondrocytes are the major native source of NO. in diarthrodial joints. Chondrocytic inducible nitric oxide synthase induced by inflammatory cytokines and bacterial cell wall fragments mediates many of the catabolic events in arthritis. Agents which specifically inhibit chondrocyte inducible NO. synthase, may thus have a role in the management in arthritis. We evaluated a novel class of potential inducible NO. synthase inhibitors, the S-substituted isothioureas, for their ability to inhibit inducible NO. synthase activity in cultured bovine chondrocytes and explants of cartilage from patients with osteoarthritis. Two isothioureas, S-methyl isothiourea and S-(aminoethyl) isothiourea were 2-4 times more potent than N(G)-monomethyl-L-arginine monoacetate, 5-10 times more potent than aminoguanidine and over 300 times more potent than N(ω)-nitro-L-arginine and N(ω)-nitro-L-arginine methyl ester. The rank order of potency of the NO. synthase inhibitors was S-(aminoethyl) isothiourea > S-methyl isothiourea > N(G)-monomethyl-L-arginine > aminoguanidine > N(ω)-nitro-L-arginine = N(ω)-nitro-L-arginine methyl ester. The order of potency was reversed (N(ω)-nitro-L-arginine methyl ester = N(ω)-nitro-L-arginine > N(G)-monomethyl-L-arginine = S-methyl isothiourea > S-(aminoethyl) isothiourea > aminoguanidine) when evaluating the same compounds ability to inhibit constitutive NO. synthase activity in bovine endothelial cells. In comparison to conventional arginine-based analogs, the isothioureas represent a more potent and relatively specific class of inhibitors of inducible NO. synthase in cartilage and thus may be beneficial in the management of arthritis.

AB - Nitric oxide (NO.) is a multifunctional messenger molecule generated by a family of enzymes, the nitric oxide synthases, and is overproduced in osteoarthritis and rheumatoid arthritis. Chondrocytes are the major native source of NO. in diarthrodial joints. Chondrocytic inducible nitric oxide synthase induced by inflammatory cytokines and bacterial cell wall fragments mediates many of the catabolic events in arthritis. Agents which specifically inhibit chondrocyte inducible NO. synthase, may thus have a role in the management in arthritis. We evaluated a novel class of potential inducible NO. synthase inhibitors, the S-substituted isothioureas, for their ability to inhibit inducible NO. synthase activity in cultured bovine chondrocytes and explants of cartilage from patients with osteoarthritis. Two isothioureas, S-methyl isothiourea and S-(aminoethyl) isothiourea were 2-4 times more potent than N(G)-monomethyl-L-arginine monoacetate, 5-10 times more potent than aminoguanidine and over 300 times more potent than N(ω)-nitro-L-arginine and N(ω)-nitro-L-arginine methyl ester. The rank order of potency of the NO. synthase inhibitors was S-(aminoethyl) isothiourea > S-methyl isothiourea > N(G)-monomethyl-L-arginine > aminoguanidine > N(ω)-nitro-L-arginine = N(ω)-nitro-L-arginine methyl ester. The order of potency was reversed (N(ω)-nitro-L-arginine methyl ester = N(ω)-nitro-L-arginine > N(G)-monomethyl-L-arginine = S-methyl isothiourea > S-(aminoethyl) isothiourea > aminoguanidine) when evaluating the same compounds ability to inhibit constitutive NO. synthase activity in bovine endothelial cells. In comparison to conventional arginine-based analogs, the isothioureas represent a more potent and relatively specific class of inhibitors of inducible NO. synthase in cartilage and thus may be beneficial in the management of arthritis.

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