2.1.1.6 (-)-epicatechin-3-gallate IC50: 0.0002 mM with 2-hydroxyestradiol as substrate, IC50: 0.0003 mM with 4-hydroxyestradiol as substrate 17280 2.1.1.6 (-)-epigallocatechin IC50: 0.044 mM with 2-hydroxyestradiol as substrate, IC50: 0.05 nM with 4-hydroxyestradiol as substrate 2241 2.1.1.6 (-)-epigallocatechin gallate potent inhibitor with epigallocatechin or 3,4-dihydroxy-L-Phe as substrates 3428 2.1.1.6 (-)-epigallocatechin gallate-4''-O-glucuronide with epigallocatechin or 3,4-dihydroxy-L-Phe as substrates 125084 2.1.1.6 (-)-epigallocatechin gallate-7-O-glucuronide with epigallocatechin or 3,4-dihydroxy-L-Phe as substrates 125083 2.1.1.6 (-)-epigallocatechin-3-gallate IC50: 70 nM with 2-hydroxyestradiol as substrate, IC50: 80 nM with 4-hydroxyestradiol as substrate, mixed inhibitor 2518 2.1.1.6 (-)-epigallocatechin-3-gallate - 2518 2.1.1.6 (-)-epigallocatechin-3-gallate-3''-O-glucuronide IC50: 0.002 mM with 2-hydroxyestradiol as substrate, IC50: 0.0025 mM with 4-hydroxyestradiol as substrate 56892 2.1.1.6 (-)-epigallocatechin-3-gallate-3'-O-glucuronide IC50: 0.0018 mM with 2-hydroxyestradiol as substrate, IC50: 0.0023 mM with 4-hydroxyestradiol as substrate 56891 2.1.1.6 (-)-epigallocatechin-3-gallate-4''-O-glucuronide IC50: 0.0025 mM with 2-hydroxyestradiol as substrate, IC50: 0.004 mM with 4-hydroxyestradiol as substrate 56893 2.1.1.6 (-)-epigallocatechin-3-gallate-7-O-glucuronide IC50: 600 nM with 2-hydroxyestradiol as substrate, IC50: 800 nM with 4-hydroxyestradiol as substrate 34895 2.1.1.6 (-)-epigallocatechin-3-O-gallate IC50: 0.05-0.07 nM for the O-methylation of 2-hydroxyestradiol, IC50: 200-500 nM for O-methylation of 4-hydroxyestradiol 1889 2.1.1.6 (-)-epigallocatechin-3-O-gallate potent non-competitive inhibitor 1889 2.1.1.6 (-)-epigallocatechin-3-O-gallate - 1889 2.1.1.6 (-)epicatechin IC50: 0.06 mM with 2-hydroxyestradiol as substrate, IC50: 0.08 mM with 4-hydroxyestradiol as substrate 42738 2.1.1.6 (-)epicatechin gallate3,5-dinitrocatechol with epigallocatechin or 3,4-dihydroxy-L-Phe as substrates 125082 2.1.1.6 (2-amino-3-methylbutanoyloxy)methyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87331 2.1.1.6 (2E)-4,7-anhydro-1,2,3-trideoxy-1-(2,3-dihydroxy-5-nitrobenzamido)-L-ribo-hept-2-enitol - 42013 2.1.1.6 (2R,3R)-5,7-bis(acetyloxy)-2-[3,4,5-tris(acetyloxy)phenyl]-3,4-dihydro-2H-chromen-3-yl 3,4-bis(acetyloxy)-5-(2-oxopropyl)benzoate - 150929 2.1.1.6 (2R,3S)-1,2,3,4-tetrahydronaphthalene-2,3-diyl bis(3,4,5-trihydroxybenzoate) - 38779 2.1.1.6 (2R,3S)-1,2,3,4-tetrahydronaphthalene-2,3-diyl bis(3,5-dihydroxybenzoate) - 26344 2.1.1.6 (2R,3S)-1,2,3,4-tetrahydronaphthalene-2,3-diyl bis[3,4,5-tris(acetyloxy)benzoate] - 150930 2.1.1.6 (2R,3S)-1,2,3,4-tetrahydronaphthalene-2,3-diyl bis[3,5-bis(acetyloxy)benzoate] - 150931 2.1.1.6 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87332 2.1.1.6 1,2-dihydroxy-4-[2-(methylamino)butyl]benzene uncompetitive inhibitor of the sCOMT isoform 77206 2.1.1.6 1-(4-butylphenyl)-5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one - 243469 2.1.1.6 1-(butyryloxy)ethyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87330 2.1.1.6 1-(isobutyryloxy)ethyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87329 2.1.1.6 1-([1,1'-biphenyl]-3-yl)-3-hydroxypyridin-4(1H)-one - 243491 2.1.1.6 1-([1,1'-biphenyl]-3-yl)-5-hydroxy-2-(1-hydroxy-2-methylpropyl)pyridin-4(1H)-one - 243492 2.1.1.6 1-([1,1'-biphenyl]-3-yl)-5-hydroxy-2-(1-hydroxybutyl)pyridin-4(1H)-one - 243493 2.1.1.6 1-([1,1'-biphenyl]-3-yl)-5-hydroxy-2-(1-hydroxyethyl)pyridin-4(1H)-one - 243494 2.1.1.6 1-([1,1'-biphenyl]-3-yl)-5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one - 243495 2.1.1.6 1-([1,1'-biphenyl]-3-yl)-5-hydroxy-2-methylpyridin-4(1H)-one - 243496 2.1.1.6 1-([1,1'-biphenyl]-3-yl)-5-hydroxy-2-phenylpyridin-4(1H)-one - 243497 2.1.1.6 1-([1,1'-biphenyl]-3-yl)-5-hydroxy-2-[hydroxy(phenyl)methyl]pyridin-4(1H)-one - 243498 2.1.1.6 1-([1,1'-biphenyl]-4-yl)-5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one - 243499 2.1.1.6 1-Carboxysalsoline i.e. 1-carboxy-1-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, competitive inhibition of 3,4-dihydroxybenzoic acid methylation 42898 2.1.1.6 1-[(5E)-5,6,7-trideoxy-7-(2,3-dihydroxy-5-nitrobenzamido)-beta-D-ribo-hept-5-enofuranosyl]-4-(trifluoromethyl)-1H-imidazole - 42012 2.1.1.6 1-[(5E)-5,6,7-trideoxy-7-(2,3-dihydroxy-5-nitrobenzamido)-beta-D-ribo-hept-5-enofuranosyl]benzo[d]imidazole - 42019 2.1.1.6 1-[(5E)-5,6,7-trideoxy-7-(2,3-dihydroxy-5-nitrobenzamido)-beta-D-ribo-hept-5-enofuranosyl]pyridin-4(1H)-one - 42023 2.1.1.6 1-[1-(2-chlorobenzyl)-1H-benzimidazol-4-yl]-3-hydroxypyridin-4(1H)-one - 206218 2.1.1.6 1-[3,4-dihydroxy-5-nitrophenyl]-2-phenyl-ethanone - 56895 2.1.1.6 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]-5-hydroxy-2-(1-hydroxyethyl)pyridin-4(1H)-one - 206217 2.1.1.6 13-hydroxy-36-(trifluoromethyl)-14H-[11,22:24,32-terpyridin]-14-one - 243537 2.1.1.6 2-Hydroxyestradiol-17beta 3-methyl ether product inhibition 91057 2.1.1.6 2-hydroxyoestrogen - 143777 2.1.1.6 2-Iodosobenzoic acid - 29394 2.1.1.6 2-methoxyestradiol-17beta product inhibition 43154 2.1.1.6 3,4,5-trihydroxypyrogallol liver homogenate, 0.03 mM inhibitor: 0.8% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169270 2.1.1.6 3,4-dihydroxymethamphetamine uncompetitive inhibitor of the sCOMT isoform 77208 2.1.1.6 3,5-dinitrocatechol liver S-COMT, 50% inhibition at 74 nM 13254 2.1.1.6 3,5-dinitrocatechol uncompetitive inhibitor 13254 2.1.1.6 3-Carboxysalsolinol - 91388 2.1.1.6 3-chloro-5,6-dihydroxy-7-nitro-1-benzothiophene-2-carboxylic acid - 87323 2.1.1.6 3-fluoro-4-[1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]benzene-1,2-diol liver homogenate, 0.03 mM inhibitor: 32.3% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169272 2.1.1.6 3-hydroxy-4'-phenyl-4H-[1,2'-bipyridin]-4-one potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid and dihydroxyphenylacetic acid 243703 2.1.1.6 3-nitro-5-(1-p-tolyl-1H-pyrazol-5-yl)benzene-1,2-diol liver homogenate, 0.003 mM inhibitor: 0% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169280 2.1.1.6 3-nitro-5-(1-phenyl-1H-pyrazol-5-yl)benzene-1,2-diol liver homogenate, 0.003 mM inhibitor: 0% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169282 2.1.1.6 3-nitro-5-(1H-pyrazol-5-yl)benzene-1,2-diol liver homogenate, 0.003 mM inhibitor: 0% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169268 2.1.1.6 4''-O-methyl epigallocatechin gallate potent inhibitor with epigallocatechin or 3,4-dihydroxy-L-Phe as substrates 34896 2.1.1.6 4',3'',4''-tri-O-methyl epigallocatechin gallate substrate: epigallocatechin 125081 2.1.1.6 4',4''-di-O-methyl epigallocatechin gallate potent inhibitor with epigallocatechin or 3,4-dihydroxy-L-Phe as substrates 56896 2.1.1.6 4'-(1-benzyl-1H-pyrazol-4-yl)-3-hydroxy-4H-[1,2'-bipyridin]-4-one - 243711 2.1.1.6 4'-(3,4-dichlorophenyl)-3-hydroxy-4H-[1,2'-bipyridin]-4-one - 243712 2.1.1.6 4'-4''-di-O-methyl-epigallocatechin-3-gallate IC50: 0.00015 mM with 2-hydroxyestradiol or 4-hydroxyestradiol as substrate, competitive with respect S-adenyosylmethionine, noncompetitive with respect to catechol 56890 2.1.1.6 4'-fluoro-3-hydroxy-5'-phenyl-4H-[1,3'-bipyridin]-4-one - 243713 2.1.1.6 4'-fluoro-4,5-dihydroxy-biphenyl-3-carboxylic acid [(E)-3-[(2S,4R,5R)-4-hydroxy-5-(6-methyl-purin-9-yl)-tetrahydro-furan-2-yl]-allyl]-amide - 87521 2.1.1.6 4'-fluoro-4,5-dihydroxy-biphenyl-3-carboxylic acid [(E)-3-[(2S,4R,5R)-4-hydroxy-5-(6-methylamino-purin-9-yl)-tetrahydro-furan-2-yl]-allyl]-amide - 87500 2.1.1.6 4'-O-methyl-(-)-epigallocatechin IC50: 0.032 mM with 2-hydroxyestradiol as substrate, IC50: 0.04 mM with 4-hydroxyestradiol as substrate 56894 2.1.1.6 4'-O-methyl-epigallocatechin-3-gallate IC50: 0.0001 mM with 2-hydroxyestradiol or 4-hydroxyestradiol as substrate 56889 2.1.1.6 4-(1-phenyl-1H-pyrazol-5-yl)benzene-1,2,3-triol liver homogenate, 0.03 mM inhibitor: 26.8% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169271 2.1.1.6 4-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazol-1-yl)benzonitrile liver homogenate, 0.003 mM inhibitor: 0.3% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169278 2.1.1.6 4-(tert-octyl)phenol causes significant inhibition of enzyme activity 155297 2.1.1.6 4-hydroxyequilenin inhibits its own methylation by COMT at higher concentrations in the presence of the reducing agent dithiothreitol, irreversible inhibitor, the inhibitor causes formation of intermolecular disulfide bonds, cys33 in recombinant human soluble COMT is the residue most likely modified by the inhibitor 17699 2.1.1.6 4-nitrocatechol - 1492 2.1.1.6 4-phenyl-7,8-dihydroxycoumarin - 155301 2.1.1.6 4-[1-(4-methylphenyl)-1H-pyrazol-5-yl]benzene-1,2-diol liver homogenate, 0.03 mM inhibitor: 41.2% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169274 2.1.1.6 4-[4-(4-chlorophenyl)-5-methyl-1H-pyrazol-3-yl]benzene-1,2,3-triol liver homogenate, 0.003 mM inhibitor: 15.6% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169279 2.1.1.6 5-(1-methyl-1H-pyrazol-5-yl)-3-nitrobenzene-1,2-diol liver homogenate, 0.003 mM inhibitor: 1.1% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169275 2.1.1.6 5-(cyclopentylsulfonyl)-7-fluoroquinolin-8-ol compound displays good pharmacokinetics in rats. pIC50 value 8.7 for membrane-bound form, 5.6 for soluble form 243837 2.1.1.6 5-hydroxy-1-[3-(isoquinolin-4-yl)phenyl]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one - 206216 2.1.1.6 5-hydroxy-2-(thiophen-2-yl)pyrimidin-4(1H)-one - 243853 2.1.1.6 5-Substituted 3-hydroxy-4-methoxybenzaldehydes - 91969 2.1.1.6 5-Substituted 3-hydroxy-4-methoxybenzoic acids - 91970 2.1.1.6 5-[(5E)-5,6,7-trideoxy-7-(2,3-dihydroxy-5-nitrobenzamido)-beta-D-ribo-hept-5-enofuranosyl]-5H-imidazo[4,5-c]pyridine - 42015 2.1.1.6 5-[(5E)-5,6,7-trideoxy-7-(2,3-dihydroxy-5-nitrobenzamido)-beta-D-ribo-hept-5-enofuranosyl]-5H-pyrrolo[3,2-c]pyridine - 42016 2.1.1.6 5-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-2,3-dihydroxybenzoic acid liver homogenate, 0.03 mM inhibitor: 24.1% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169273 2.1.1.6 5-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-3-nitrobenzene-1,2-diol liver homogenate, 0.003 mM inhibitor: 0% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169281 2.1.1.6 5-[1-(3-chlorophenyl)-4-phenyl-1H-pyrazol-5-yl]-3-nitrobenzene-1,2-diol liver homogenate, 0.003 mM inhibitor: 68.6% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169277 2.1.1.6 6-methyl-9-[(5E)-5,6,7-trideoxy-7-[5-(4-fluorophenyl)-2,3-dihydroxybenzamido]-beta-D-ribo-hept-5-enofuranosyl]purine - 42020 2.1.1.6 7-chloro-5-((4-fluorophenyl)sulfonyl)quinolin-8-ol compound exhibits very low clearance and long half-life in rat pharmacokinetics studies. pIC50 value 6.7 for membrane-bound form, below 5 for soluble form 243902 2.1.1.6 7-chloro-5-(cyclopentylsulfonyl)quinolin-8-ol compound exhibits very low clearance and long half-life in rat pharmacokinetics studies. pIC50 value 7.7 for membrane-bound form, below 5 for soluble form 243903 2.1.1.6 7-chloro-5-(pyrrolidin-1-ylsulfonyl)quinolin-8-ol compound exhibits very low clearance and long half-life in rat pharmacokinetics studies . pIC50 value 8.0 for membrane-bound form, 5.5 for soluble form 243904 2.1.1.6 7-fluoro-5-(pyrrolidin-1-ylsulfonyl)quinolin-8-ol compound displays good pharmacokinetics in rats. pIC50 value 8.4 for membrane-bound form, 5.8 for soluble form 243905 2.1.1.6 8-O-methyldaphnetin 0.1 mM, about 20% residual activity. 8-O-methyldaphnetin has no effect on Km but decreases Vmax 243923 2.1.1.6 9-hydroxypyrido[2,1-c][1,4]benzothiazin-8(6H)-one - 243937 2.1.1.6 9-[(5E)-3,5,6,7-tetradeoxy-3-fluoro-7-[5-(4-fluorophenyl)-2,3-dihydroxybenzamido]-beta-D-xylo-hept-5-enofuranosyl]-N6-methyladenine - 87522 2.1.1.6 9-[(5E)-3,5,6,7-tetradeoxy-7-[5-(4-fluorophenyl)-2,3-dihydroxybenzamido]-3-methyl-beta-D-xylo-hept-5-enofuranosyl]-N6-propyladenine - 87523 2.1.1.6 9-[(5E)-5,6,7-trideoxy-7-(2,3-dihydroxy-5-nitrobenzamido)-beta-D-ribo-hept-5-enofuranosyl]purine - 42014 2.1.1.6 amino group reagents - 20992 2.1.1.6 Analogs of S-adenosyl-L-homocysteine overview: inhibition of the liver, heart and brain enzyme 96154 2.1.1.6 ascorbic acid - 387 2.1.1.6 benzyl butyl phthalate causes significant inhibition of enzyme activity 155298 2.1.1.6 benzyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87328 2.1.1.6 beta-thujaplicin 70-100% inhibition at 0.2 mM 12456 2.1.1.6 butyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87326 2.1.1.6 butyryloxymethyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87321 2.1.1.6 Ca2+ - 15 2.1.1.6 Ca2+ quantum mechanical/molecular mechanical dynamics study 15 2.1.1.6 caffeic acid - 426 2.1.1.6 caffeic acid COMT from liver, using 2-hydroxyestradiol as substrate, in Tris-HCl buffer (10 mM, pH 7.4), at 37°C; COMT from liver, using 4-hydroxyestradiol as substrate, in Tris-HCl buffer (10 mM, pH 7.4), at 37°C; COMT from placenta, using 2-hydroxyestradiol as substrate, in Tris-HCl buffer (10 mM, pH 7.4), at 37°C; COMT from placenta, using 4-hydroxyestradiol as substrate, in Tris-HCl buffer (10 mM, pH 7.4), at 37°C 426 2.1.1.6 caffeic acid phenethyl ester COMT from liver, using 2-hydroxyestradiol as substrate, in Tris-HCl buffer (10 mM, pH 7.4), at 37°C; COMT from liver, using 4-hydroxyestradiol as substrate, in Tris-HCl buffer (10 mM, pH 7.4), at 37°C 11671 2.1.1.6 catechin IC50: 14-17 nM for the O-methylation of 2-hydroxyestradiol, IC50: 0.005-0.007 mM for O-methylation of 4-hydroxyestradiol 1437 2.1.1.6 catechin IC50: 0.00164 mM 1437 2.1.1.6 catechin - 1437 2.1.1.6 catechol - 156 2.1.1.6 CGP 28014 - 143779 2.1.1.6 chlorogenic acid COMT from liver, using 2-hydroxyestradiol as substrate, in Tris-HCl buffer (10 mM, pH 7.4), at 37°C; COMT from liver, using 4-hydroxyestradiol as substrate, in Tris-HCl buffer (10 mM, pH 7.4), at 37°C; COMT from placenta, using 2-hydroxyestradiol as substrate, in Tris-HCl buffer (10 mM, pH 7.4), at 37°C; COMT from placenta, using 4-hydroxyestradiol as substrate, in Tris-HCl buffer (10 mM, pH 7.4), at 37°C 592 2.1.1.6 chrysin slight inhibition at 0.3 mM 1727 2.1.1.6 Cistus parviflorus leaf extract mixed type inhibition 169706 2.1.1.6 daidzein soy isoflavones at hormonally active concentrations cause a significant reduction of both COMT mRNA levels and COMT activity as well as of the methylation of 4-hydroxyestradiol 848 2.1.1.6 daphnetin 0.1 mM, about 10% residual activity 8088 2.1.1.6 dibutyl phthalate causes significant inhibition of enzyme activity 18433 2.1.1.6 dihydromyricetin competitive 7400 2.1.1.6 diisononyl phthalate causes significant inhibition of enzyme activity 155299 2.1.1.6 dioctyl phthalate causes significant inhibition of enzyme activity 155300 2.1.1.6 dobutamine competitive to dopamine 11198 2.1.1.6 dopamine competitive to dobutamine 242 2.1.1.6 entacapone - 17740 2.1.1.6 entacapone 0.001 mM, about 10% residual activity 17740 2.1.1.6 epicatechin IC50: 44-65 nM for the O-methylation of 2-hydroxyestradiol, IC50: 0.01-0.018 mM for O-methylation of 4-hydroxyestradiol 1161 2.1.1.6 epicatechin IC50: 0.00196 mM 1161 2.1.1.6 epicatechin - 1161 2.1.1.6 epigallocatechin - 2229 2.1.1.6 epigallocatechin-3-gallate inhibition in vitro. Supplementation with a high dose does not impair the activity of COMT 2607 2.1.1.6 Fe3+ quantum mechanical/molecular mechanical dynamics study 70 2.1.1.6 fisetin IC50: 0.0033-0.0045 nM for the O-methylation of 2-hydroxyestradiol, IC50: 0.0026-0.0042 nM for O-methylation of 4-hydroxyestradiol 1257 2.1.1.6 fisetin - 1257 2.1.1.6 flavone IC50: 0.00549 mM 1617 2.1.1.6 flavonoids overview: relationship between structure and ability to inhibit 16286 2.1.1.6 gallic acid - 764 2.1.1.6 Gallic acid methylester - 93429 2.1.1.6 genistein slight inhibition at 0.3 mM 377 2.1.1.6 genistein soy isoflavones at hormonally active concentrations cause a significant reduction of both COMT mRNA levels and COMT activity as well as of the methylation of 4-hydroxyestradiol 377 2.1.1.6 Harmaline - 5974 2.1.1.6 harmalol - 16542 2.1.1.6 Hg2+ complete inhibition at 1 mM 33 2.1.1.6 high ionic strength - 3693 2.1.1.6 homocysteine - 747 2.1.1.6 iodoacetamide slight 67 2.1.1.6 iodoacetic acid - 213 2.1.1.6 isobutyryloxymethyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87334 2.1.1.6 isopropyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87327 2.1.1.6 L-ascorbic acid - 974 2.1.1.6 L-Dopa - 320 2.1.1.6 lactoferrin bovine lactoferrin binds to and inhibits COMT using its N-terminal region. A fragment of the lactoferrin N-terminal residues 6-50, with two pairs of disulfide bonds, shows higher inhibitory activity than intact lactoferrin. Lactoferrin does not compete with S-adenosylmethionine. COMT activity in the cell extracts form Caco-2 and HepG2 cells is inhibited by lactoferrin and the N-terminal fragment 10970 2.1.1.6 methyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87324 2.1.1.6 Mg2+ inhibition above 2 mM; required for activity 6 2.1.1.6 Mg2+ required for activity 6 2.1.1.6 additional information inhibition by analogs of S-adenosyl-homcysteine 2 2.1.1.6 additional information relationship between the structure of flavonoids and their inhibitory activity 2 2.1.1.6 additional information substrate inhibition is dependent on the concentration of S-adenosylmethionine and MgCl2 2 2.1.1.6 additional information activity of the enzyme is strongly influenced by the nature of the buffer 2 2.1.1.6 additional information no inhibition by genistein, daidzein and biochanin A 2 2.1.1.6 additional information role of COMT inhibitors in Parkinson’s disease as a new therapeutic approach to Parkinson’s disease involving conversion of levodopa to dopamine at the target region in the brain and facilitation of the continuous action of this amine at the receptor sites. A historical overview of the discovery and development of COMT inhibitors is presented with a special emphasis on nebicapone, presently under clinical development, as well as entacapone and tolcapone, which are already approved as adjuncts in the therapy of Parkinson’s disease. This article reviews human pharmacokinetic and pharmacodynamic properties of these drugs as well as their clinical efficacy and safety 2 2.1.1.6 additional information COMT is a target for inhibitor development aiming at Parkinson’s disease treatment and is submitted to extensive structure-based drug design 2 2.1.1.6 additional information (-)-epigallocatechin is not active even at a concentration of 0.05 mM 2 2.1.1.6 additional information COMT activity appears unaffected by loss of the dopaminergic nigrostriatal pathway and levodopa treatment 2 2.1.1.6 myricetin competitive 484 2.1.1.6 Myricitrin competitive 8143 2.1.1.6 N-(2-[2-[(2R,3S,4R,5R)-5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-ethoxy]-ethyl)-2,3-dihydroxy-5-nitro-benzamide IC50: 0.002 mM 56682 2.1.1.6 N-(3,4-Dihydroxyphenyl)maleimide irreversible 94141 2.1.1.6 N-(3,4-Dihydroxyphenyl)succinimide reversible 94142 2.1.1.6 N-ethyl-1-[(5E)-5,6,7-trideoxy-7-[5-(4-fluorophenyl)-2,3-dihydroxybenzamido]-beta-D-ribo-hept-5-enofuranosyl]-1H-imidazole-4-carboxamide - 42011 2.1.1.6 N-ethyl-3,4-dihydroxyamphetamine uncompetitive inhibitor of the sCOMT isoform 77207 2.1.1.6 N-ethylmaleimide - 49 2.1.1.6 N-ethylmaleimide 70-100% inhibition at 0.2 mM 49 2.1.1.6 N-ethylmaleimide complete inhibition at 1 mM 49 2.1.1.6 N-methyl-1-[(5E)-5,6,7-trideoxy-7-[5-(4-fluorophenyl)-2,3-dihydroxybenzamido]-beta-D-ribo-hept-5-enofuranosyl]-1H-1,2,4-triazole-3-carboxamide - 42018 2.1.1.6 N-methyl-1-[(5E)-5,6,7-trideoxy-7-[5-(4-fluorophenyl)-2,3-dihydroxybenzamido]-beta-D-ribo-hept-5-enofuranosyl]-1H-imidazole-4-carboxamide - 42021 2.1.1.6 N-[(2E)-3-[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(methylamino)-9H-purin-9-yl]tetrahydrofuran-2-yl]prop-2-en-1-yl]-4'-fluoro-4,5-dihydroxybiphenyl-3-carboxamide - 87322 2.1.1.6 N-[(2E)-3-[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(propylamino)-9H-purin-9-yl]tetrahydrofuran-2-yl]prop-2-en-1-yl]-4'-fluoro-4,5-dihydroxybiphenyl-3-carboxamide - 87525 2.1.1.6 N-[(2E)-3-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-en-1-yl]-2,3-dihydroxy-5-nitrobenzamide - 19644 2.1.1.6 N-[(2E)-3-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-en-1-yl]-4'-fluoro-4,5-dihydroxybiphenyl-3-carboxamide - 19643 2.1.1.6 N-[(2E)-3-[(2R,3S,4R,5R)-5-(6-ethyl-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-en-1-yl]-4'-fluoro-4,5-dihydroxybiphenyl-3-carboxamide - 87306 2.1.1.6 N-[(2E)-3-[(2R,3S,4R,5R)-5-[6-(cyclopropylamino)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-en-1-yl]-4'-fluoro-4,5-dihydroxybiphenyl-3-carboxamide - 87451 2.1.1.6 N-[(2E)-3-[(2R,3S,4R,5R)-5-[6-(ethylamino)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl]prop-2-en-1-yl]-4'-fluoro-4,5-dihydroxybiphenyl-3-carboxamide - 87524 2.1.1.6 N-[(2E)-3-[(2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl]prop-2-en-1-yl]-2,3-dihydroxy-5-nitrobenzamide - 87519 2.1.1.6 N-[(2E)-3-[(2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl]prop-2-en-1-yl]-2,3-dihydroxy-5-nitrobenzamide - 87520 2.1.1.6 N-[(E)-4-[(2R,3S,4R,5R)-5-(6-Amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-but-2-enyl]-2,3-dihydroxy-5-nitro-benzamide IC50: 9 nM 56683 2.1.1.6 N-[2-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]ethyl]-2,3-dihydroxy-5-nitrobenzene-1-carboxamide IC50: 60 nM 56898 2.1.1.6 N-[3-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]propyl]2,3-dihydroxy-5-nitrobenzene-1-carboxamide IC50: 200 nM 56899 2.1.1.6 N-[4-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]butyl]-2,3-dihydroxy-5-nitrobenzene-1-carboxamide IC50: 0.005 mM 56900 2.1.1.6 N-[[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl]-2,3-dihydroxy-5-nitrobenzene-1-carboxamide IC50: 0.09 mM, very potent bisubstrate inhibitor 56897 2.1.1.6 N6-methyl-9-[(5E)-5,6,7-trideoxy-7-(2,3-dihydroxy-5-nitrobenzamido)-beta-D-ribo-hept-5-enofuranosyl]adenine - 42017 2.1.1.6 nebicapone - 143778 2.1.1.6 nitecapone - 68972 2.1.1.6 nordihydroguaiaretic acid - 926 2.1.1.6 norepinephrine 0.01 mM, 41% inhibition of 2-hydroxyestradiol methylation 975 2.1.1.6 OR-462 disubstituted catechol 94567 2.1.1.6 OR486 depressed COMT activity results in enhanced mechanical and thermal pain sensitivity 143776 2.1.1.6 p-chloromercuribenzoate - 43 2.1.1.6 p-chloromercuribenzoate complete inhibition at 1 mM 43 2.1.1.6 p-hydroxymercuribenzoate 70-100% inhibition at 0.2 mM 98 2.1.1.6 Peganum harmala seed extract mixed type inhibition 169708 2.1.1.6 Phenolic compounds - 98528 2.1.1.6 Polyphenolic compounds - 98539 2.1.1.6 propyl-3-chloro-5,6-dihydroxy-7-nitrobenzo[b]thiophene-2-carboxylate - 87325 2.1.1.6 purpurogallin - 5210 2.1.1.6 purpurogallin decreased Vmax and increased Km-value 5210 2.1.1.6 purpurogallin carboxylic acid - 125085 2.1.1.6 pyridin-4-yl (5E)-5,6,7-trideoxy-7-(2,3-dihydroxy-5-nitrobenzamido)-1-thio-beta-D-ribo-hept-5-enofuranoside - 42022 2.1.1.6 pyrogallol 70-100% inhibition at 0.2 mM 658 2.1.1.6 pyrogallol - 658 2.1.1.6 quercetin IC50: 0.0085 mM with 2-hydroxyestradiol or 4-hydroxyestradiol as substrate 137 2.1.1.6 quercetin IC50: 0.0009-0.0015 mM for the O-methylation of 2-hydroxyestradiol, IC50: 0.0005-0.0012 mM for O-methylation of 4-hydroxyestradiol 137 2.1.1.6 quercetin 0.01 mM, 90% inhibition of 2-hydroxyestradiol methylation 137 2.1.1.6 quercetin IC50: 0.00048 mM 137 2.1.1.6 quercetin - 137 2.1.1.6 Ro 41-0960 - 13298 2.1.1.6 Ro 41-0960 IC50: 5-42 nM 13298 2.1.1.6 RO-4-4602 competitive 20819 2.1.1.6 Ro41-0960 blocks the methoxylation of catechol estrogens, with concomitant 3fold to 4fold increases in the levels of the depurinating adducts. Low activity of COMT leads to higher levels of depurinating estrogen-DNA adducts that can induce mutations and initiate cancer 37752 2.1.1.6 Ro41-0960 - 37752 2.1.1.6 Ro41-0960 depressed COMT activity results in enhanced mechanical and thermal pain sensitivity 37752 2.1.1.6 S-adenosyl-L-homocysteine - 36 2.1.1.6 S-adenosyl-L-homocysteine 50% inhibition at about 0.005 mM 36 2.1.1.6 S-adenosyl-L-methionine - 24 2.1.1.6 Salsolidine i.e. 1-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, competitive inhibition of 3,4-dihydroxybenzoic acid methylation 20512 2.1.1.6 Salsolidine - 20512 2.1.1.6 salvianolic acid B weak inhibitor. In vivo, a single intravenous dose of salvianolic acid B decreases the plasma concentration of 3-O-methyldopa, with no obvious effect on the pharmacokinetics of L-dopa 206215 2.1.1.6 theaflavin-3,3'-digallate decreased Vmax and increased Km-value 11507 2.1.1.6 tolcapone - 23408 2.1.1.6 tolcapone possibility of genotype-targeted pharmacology for the treatment of cognitive dysfunction associated with schizophrenia. Even though tolcapone has proved useful in this regard, its hepatotoxicity proscribes its wide-spread use. The development of COMT inhibitors that can permeate the blood-brain barrier effectively and are devoid of serious adverse effects will allow expansion of the search for more specific, selective and effective therapies for the treatment of cognitive disorders 23408 2.1.1.6 tolcapone inhibitor of isoform MB-COMT, substrate of isoform S-COMT 23408 2.1.1.6 tolcapone tolcapone increases significantly the cytotoxic effect of high dose UVB irradiation in HaCat cells. High concentrations of tolcapone reduce melanin levels in melanoma cells parallel to reduced cell numbers 23408 2.1.1.6 tolcapone strongly inhibits the formation of 3-methylsalvianolic acid B in vitro and in vivo, without any change in its plasma concentration. Tolcapone significantly increases the cumulative bile excretion of salvianolic acid from 3% to 40% in the rat 23408 2.1.1.6 Triton X-100 - 61 2.1.1.6 tropolone - 1033 2.1.1.6 tropolone 70-100% inhibition at 0.2 mM 1033 2.1.1.6 tropolone complete inhibition at 0.25 mM 1033 2.1.1.6 U-0521 - 50331 2.1.1.6 Vitex agnus-cactus leaf extract mixed type inhibition 169707 2.1.1.6 [5-(3,4-dihydroxy-5-nitrophenyl)-4-phenyl-1H-pyrazol-1-yl](4-methylphenyl)methanone liver homogenate, 0.003 mM inhibitor: 2.8% metanephrine formed relative to the control in absence of inhibitor (5 min reaction time), pH 7.8, 37°C 169269