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Molecular Pharmacology

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Research ArticleArticle

The Inhibitory Potency and Selectivity of Arginine Substrate Site Nitric-Oxide Synthase Inhibitors Is Solely Determined by Their Affinity toward the Different Isoenzymes

Rainer Boer, Wolf-Rüdiger Ulrich, Thomas Klein, Berit Mirau, Sabine Haas and Ilka Baur
Molecular Pharmacology November 2000, 58 (5) 1026-1034; DOI: https://doi.org/10.1124/mol.58.5.1026
Rainer Boer
Byk Gulden Pharmaceuticals, Konstanz, Germany
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Wolf-Rüdiger Ulrich
Byk Gulden Pharmaceuticals, Konstanz, Germany
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Thomas Klein
Byk Gulden Pharmaceuticals, Konstanz, Germany
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Berit Mirau
Byk Gulden Pharmaceuticals, Konstanz, Germany
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Sabine Haas
Byk Gulden Pharmaceuticals, Konstanz, Germany
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Ilka Baur
Byk Gulden Pharmaceuticals, Konstanz, Germany
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Abstract

We have investigated various nitric oxide (NO) synthase inhibitors for their affinity and selectivity toward the three human isoenzymes in radioligand binding experiments. Therefore, we developed the new radioligand [3H]2-amino-4-picoline to measure binding of these compounds to the three human NO synthase (NOS) isoenzymes. Aminopicoline is a potent and nonselective inhibitor of all three isoforms. [3H]2-amino-4-picoline bound saturably and with high affinity to human NOSs. Affinity constants (K D values) of 59, 111, and 136 nM were obtained for the inducible, neuronal, and endothelial NOS isoforms (iNOS, nNOS, eNOS). Binding of [3H]2-amino-4-picoline was competitive with the substrate arginine. From all the inhibitors tested, AMT (2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine hydrochloride) showed the highest affinity and no selectivity.l-NIL [l-N 6-(1-Iminoethyl)lysine hydrochloride] and aminoguanidine were moderately iNOS-selective whilel-NA ( N G-nitro-l-arginine) and l-NAME(N G-nitro-l-arginine methyl ester hydrochloride) showed selectivity toward the constitutive isoforms. High iNOS versus eNOS selectivity was found for 1400W, whereas several isothiourea derivatives and 1400W displayed moderate n- versus eNOS selectivity. To relate the affinity of these compounds to their inhibitory potency, we measured the inhibitory potency under almost identical conditions using a new microtiter plate assay. The inhibitory potency of selective and nonselective NOS inhibitors was almost exactly mirrored by their affinity toward the different isoenzymes. Highly significant correlations were obtained between the potency of enzyme inhibition and the inhibition of [3H]2-amino-4-picoline binding for all three isoenzymes. These data show that the potency and selectivity of NOS inhibitors are solely determined by their affinity toward the different isoforms. Furthermore, these data identify the new radioligand [3H]2-amino-4-picoline as a very useful radiolabel for the investigation of the substrate binding site of all three isoforms.

Footnotes

    • Received February 4, 2000.
    • Accepted July 28, 2000.
  • Send reprint requests to: Dr. Rainer Boer, Byk Gulden Pharmaceuticals, Byk Gulden-Str. 2, D-78467 Konstanz, Germany. E-mail:rainer.boer{at}byk.de

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (5)
Molecular Pharmacology
Vol. 58, Issue 5
1 Nov 2000
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Research ArticleArticle

The Inhibitory Potency and Selectivity of Arginine Substrate Site Nitric-Oxide Synthase Inhibitors Is Solely Determined by Their Affinity toward the Different Isoenzymes

Rainer Boer, Wolf-Rüdiger Ulrich, Thomas Klein, Berit Mirau, Sabine Haas and Ilka Baur
Molecular Pharmacology November 1, 2000, 58 (5) 1026-1034; DOI: https://doi.org/10.1124/mol.58.5.1026

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Research ArticleArticle

The Inhibitory Potency and Selectivity of Arginine Substrate Site Nitric-Oxide Synthase Inhibitors Is Solely Determined by Their Affinity toward the Different Isoenzymes

Rainer Boer, Wolf-Rüdiger Ulrich, Thomas Klein, Berit Mirau, Sabine Haas and Ilka Baur
Molecular Pharmacology November 1, 2000, 58 (5) 1026-1034; DOI: https://doi.org/10.1124/mol.58.5.1026
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