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Vol. 58, Issue 5, 1026-1034, November 2000
Byk Gulden Pharmaceuticals, Konstanz, Germany
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
(KD 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-N6-(1-Iminoethyl)lysine
hydrochloride] and aminoguanidine were moderately iNOS-selective while
L-NA
(NG-nitro-L-arginine)
and L-NAME
(NG-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.
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