A new and potent calmodulin antagonist, HF-2035, which inhibits vascular relaxation induced by nitric oxide synthase
HF-2035, 2-[ N-(2-aminoethyl)- N-(2,4,5-trichlorobenzenesulfonyl)] amino- N-(4-chlorocinnamyl)- N-methylbenzylamine, was synthesized and its effects on calmodulin-dependent enzymes were investigated. HF-2035 inhibited calmodulin kinase I, calmodulin kinase II and myosin light-chain kinase with IC 50...
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Published in | European journal of pharmacology Vol. 299; no. 1; pp. 119 - 126 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
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Elsevier B.V
28.03.1996
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Abstract | HF-2035, 2-[
N-(2-aminoethyl)-
N-(2,4,5-trichlorobenzenesulfonyl)] amino-
N-(4-chlorocinnamyl)-
N-methylbenzylamine, was synthesized and its effects on calmodulin-dependent enzymes were investigated. HF-2035 inhibited calmodulin kinase I, calmodulin kinase II and myosin light-chain kinase with IC
50 values of 1.3 μM, 1.6 μM and 68 μM, respectively. HF-2035 also inhibited the activity of recombinant rat neuronal nitric oxide synthase, one of the calmodulin-dependent enzymes, with a
K
i of 0.78 μM. Partially purified nitric oxide synthase of rat brain was also inhibited by HF-2035 with an IC
50 of 3.2 μM. Kinetic analysis indicated that this inhibitory effect of HF-2035 was competitive with respect to calmodulin. We examined the effects of HF-2035 on constitutive nitric oxide synthase in a bioassay using vascular strips of rabbit carotid artery with and without endothelium. HF-2035 inhibited acetylcholine- and calcium ionophore, A23187 (6
S-[6α(2
S∗,3
S∗),8β(
R∗),9β,11α]-5-(methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1
H-pyrrol-2-yl-ethyl]-1,7-d methyl]-4-benzoxazolecarboxylic acid)-induced relaxation of endothelium-intact strips with an ED
50 of 1.5 ± 0.5 μM and 2.8 ± 1 μM, respectively. This compound, however, did not inhibit
N-nitroso-
N-morpholinoaminoacetonitrile (SIN-1A), an exogenous nitric oxide donor, -induced relaxation of endothelium-denuded strips. W-7 (
N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide) inhibited acetylcholine-induced relaxation with an ED
50 of 46 ± 7 μM, which was 30-fold less potent than HF-2035. HF-2035 was unable to inhibit the activity of the inducible form of nitric oxide synthase in isolated thoracic aorta of rat treated with
Escherichia coli lipopolysaccharide. These findings suggest that HF-2035 is a new and potent calmodulin antagonist, and may be used as a mother compound to develop more selective inhibitors of constitutive nitric oxide synthase. |
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AbstractList | HF-2035, 2-[N-(2-aminoethyl)-N-(2,4,5-trichlorobenzenesulfonyl)] amino-N-(4-chlorocinnamyl)-N-methylbenzylamine, was synthesized and its effects on calmodulin-dependent enzymes were investigated. HF-2035 inhibited calmodulin kinase I, calmodulin kinase II and myosin light-chain kinase with IC50 values of 1.3 microM, 1.6 microM and 68 microM, respectively. HF-2035 also inhibited the activity of recombinant rat neuronal nitric oxide synthase, one of the calmodulin-dependent enzymes, with a Ki of 0.78 microM. Partially purified nitric oxide synthase of rat brain was also inhibited by HF-2035 with an IC50 of 3.2 microM. Kinetic analysis indicated that this inhibitory effect of HF-2035 was competitive with respect to calmodulin. We examined the effects of HF-2035 on constitutive nitric oxide synthase in a bioassay using vascular strips of rabbit carotid artery with and without endothelium. HF-2035 inhibited acetylcholine- and calcium ionophore, A23187 (6S-[6 alpha (2S*,3S*),8 beta (R*),9 beta, 11 alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)- ethyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazol ecarboxylic acid)-induced relaxation of endothelium-intact strips with an ED50 of 1.5 +/- 0.5 microM and 2.8 +/- 1 microM, respectively. This compound, however, did not inhibit N-nitroso-N-morpholinoaminoacetonitrile (SIN-1A), an exogenous nitric oxide donor, -induced relaxation of endothelium-denuded strips. W-7 (N-(6-aminohexyl)-5-chloro-1- naphthalenesulfonamide) inhibited acetylcholine-induced relaxation with an ED50 of 46 +/- 7 microM, which was 30-fold less potent than HF-2035. HF-2035 was unable to inhibit the activity of the inducible form of nitric oxide synthase in isolated thoracic aorta of rat treated with Escherichia coli lipopolysaccharide. These findings suggest that HF-2035 is a new and potent calmodulin antagonist, and may be used as a mother compound to develop more selective inhibitors of constitutive nitric oxide synthase. HF-2035, 2-[ N-(2-aminoethyl)- N-(2,4,5-trichlorobenzenesulfonyl)] amino- N-(4-chlorocinnamyl)- N-methylbenzylamine, was synthesized and its effects on calmodulin-dependent enzymes were investigated. HF-2035 inhibited calmodulin kinase I, calmodulin kinase II and myosin light-chain kinase with IC 50 values of 1.3 μM, 1.6 μM and 68 μM, respectively. HF-2035 also inhibited the activity of recombinant rat neuronal nitric oxide synthase, one of the calmodulin-dependent enzymes, with a K i of 0.78 μM. Partially purified nitric oxide synthase of rat brain was also inhibited by HF-2035 with an IC 50 of 3.2 μM. Kinetic analysis indicated that this inhibitory effect of HF-2035 was competitive with respect to calmodulin. We examined the effects of HF-2035 on constitutive nitric oxide synthase in a bioassay using vascular strips of rabbit carotid artery with and without endothelium. HF-2035 inhibited acetylcholine- and calcium ionophore, A23187 (6 S-[6α(2 S∗,3 S∗),8β( R∗),9β,11α]-5-(methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1 H-pyrrol-2-yl-ethyl]-1,7-d methyl]-4-benzoxazolecarboxylic acid)-induced relaxation of endothelium-intact strips with an ED 50 of 1.5 ± 0.5 μM and 2.8 ± 1 μM, respectively. This compound, however, did not inhibit N-nitroso- N-morpholinoaminoacetonitrile (SIN-1A), an exogenous nitric oxide donor, -induced relaxation of endothelium-denuded strips. W-7 ( N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide) inhibited acetylcholine-induced relaxation with an ED 50 of 46 ± 7 μM, which was 30-fold less potent than HF-2035. HF-2035 was unable to inhibit the activity of the inducible form of nitric oxide synthase in isolated thoracic aorta of rat treated with Escherichia coli lipopolysaccharide. These findings suggest that HF-2035 is a new and potent calmodulin antagonist, and may be used as a mother compound to develop more selective inhibitors of constitutive nitric oxide synthase. |
Author | Kato, Masumi Watanabe, Yasuo Saito, Nozomi Hidaka, Hiroyoshi Win, Nang Hla Hla Iida, Yuji Ishikawa, Tomohiko Yokokura, Hisayuki |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/8901014$$D View this record in MEDLINE/PubMed |
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CitedBy_id | crossref_primary_10_1016_S0165_6147_97_01064_X crossref_primary_10_1152_ajpheart_00932_2001 crossref_primary_10_1016_S0167_4838_98_00191_5 crossref_primary_10_1080_00365519709056377 |
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Keywords | W-7 Calmodulin antagonist HF-2035 Nitric oxide (NO) synthase inhibitor Vascular relaxation |
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Snippet | HF-2035, 2-[
N-(2-aminoethyl)-
N-(2,4,5-trichlorobenzenesulfonyl)] amino-
N-(4-chlorocinnamyl)-
N-methylbenzylamine, was synthesized and its effects on... HF-2035, 2-[N-(2-aminoethyl)-N-(2,4,5-trichlorobenzenesulfonyl)] amino-N-(4-chlorocinnamyl)-N-methylbenzylamine, was synthesized and its effects on... |
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SubjectTerms | Acetylcholine - pharmacology Animals Benzenesulfonates - pharmacology Benzylamines - pharmacology Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors Calmodulin - antagonists & inhibitors Calmodulin antagonist Endothelium, Vascular - drug effects HF-2035 In Vitro Techniques Male Muscle Relaxation Muscle, Smooth, Vascular - drug effects Nitric oxide (NO) synthase inhibitor Nitric Oxide Synthase - antagonists & inhibitors Rabbits Rats Rats, Sprague-Dawley Sulfonamides - pharmacology Vascular relaxation Vasodilation - drug effects Vasodilator Agents - pharmacology W-7 |
Title | A new and potent calmodulin antagonist, HF-2035, which inhibits vascular relaxation induced by nitric oxide synthase |
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