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PubMed1985

Catechol estrogen formation by pig blastocysts during the preimplantation period: biochemical characterization of estrogen-2/4-hydroxylase and correlation with aromatase activity.

Formation of the catechol estrogens 2- and 4-hydroxyestradiol (2-OHE2 and 4-OHE2) from estradiol by pig blastocysts was studied using a direct product isolation assay for estrogen-2/4-hydroxylase (E-2/4-H). Blastocyst E-2/4-H activity was characterized biochemically using homogenates of blastocysts obtained on day 12 of pregnancy. This information was used to establish appropriate incubation conditions for the assay of E-2/4-H activity in blastocysts during the preimplantation period. Catechol estrogen formation was linear with time for up to 30 min and with blastocyst protein concentrations of up to 100 micrograms in a reaction volume of 150 microliters. The E-2/4-H activity of pig blastocysts was maximal at pH 7.9 and was not affected by the nonionic detergent Tween-80. The E-2/4-H activity was dependent on nicotinamide cofactor, with NADPH preferred over NADH for 2-OHE2 formation. The predominant catechol estrogen formed was 2-OHE2: maximum velocities (Vmax) for the formation of 2- and 4-OHE2 were 1570 and 174 pmol/mg protein . 30 min, respectively. The apparent Km values with respect to estradiol for 2- and 4-OHE2 were similar, 4.39 and 4.27 microM, respectively. Blastocyst E-2/4-H activity was detectable in one of two samples of blastocysts from day 10 of pregnancy (4.4 pmol 2-OHE2/mg protein . 30 min), increased to a maximum on days 12 and 13 (628 +/- 153 and 516 +/- 227 pmol 2-OHE2/mg protein . 30 min, respectively), and declined by day 14 (63.2 +/- 32.9 pmol 2-OHE2/mg protein . 30 min). The activity of E-2/4-H was positively correlated with aromatase activity assayed in the same tissue samples from days 10-14 of pregnancy. The surge in E-2/4-H activity coincides with several of the critical events that occur near the time of implantation. Our findings are consistent with the hypothesis that catechol estrogens mediate some of the actions of estrogens in early pregnancy in the pig.

Animals↗
PubMed2005

Production of catechol-siderophore and utilization of transferrin-bound iron in Bacillus cereus.

In the present study we attempted to ascertain whether Bacillus cereus was able to produce catechol-siderophore(s), and whether it was able to utilize transferrin-bound iron. The growth of B. cereus was stimulated in proportion to the iron-saturation level of the transferrin, and catechol-siderophores were produced in inverse proportion to this level. B. cereus was proved to uptake iron from partially iron-saturated transferrin or holotransferrin, without destroying the transferrin by its proteases. The catechol-siderophores from B. cereus were able to sustain and augment its growth on the transferrin-bound iron. These results indicate that B. cereus has the ability to produce catechol-siderophores, and to utilize transferrin-bound iron as an iron source for growth, via the siderophore-mediated iron-uptake system.

Bacillus cereus↗
PubMed2004

Potentiometric and spectroscopic studies on aluminium(III) complexes of some catechol derivatives.

The interactions of aluminium(III) ion with the triprotic catechol derivatives (H3L), 2,3-dihydroxybenzoic acid (2,3-DHBA), 3,4-dihydroxyphenylacetic acid (3,4-DHPA), 3,4-dihydroxybenzoic acid (3,4-DHBA), and 3,4-dihydroxyhydrocinnamic acid (3,4-DHHCA) were investigated in aqueous solution at 25.0 degrees C. The Calvin-Bjerrum titration method was adopted for the determination of formation constants of proton-ligand and aluminium(III)-ligand complexes. Potentiometric and spectroscopic results indicated that these catechol derivatives exhibit a true bidentate character. The chelation occurs via their catecholate sites, with the exception of 2,3-DHBA. In the case of 2,3-DHBA complexes, the dominant species are either the salicylate type (COO-, O-) or catecholate type (O-, O-) complex. The protonation constants of ligands and their formation constants of Al(III) complexes were also correlated. The order of decreasing stabilities of complexes is: 3,4-DHPA>3,4-DHBA>3,4-DHHCA>2,3-DHBA.

Aluminum Compounds↗
PubMed1994

Catechol estrogens are more potent antioxidants than estrogens for the Cu(2+)-catalyzed oxidation of low or high density lipoprotein: antioxidative effects of steroids on lipoproteins.

In order to clarify the mechanism of antiatherogenic action of several steroids such as estrogens, dehydroepiandrosterone (DHEA) and dexamethasone, we investigated the effects of various steroids on the copper (Cu2+)-catalyzed oxidation of low density lipoprotein (LDL) or high density lipoprotein (HDL) in 0.15 M NaCl by measuring thiobarbituric acid-reactive substances (TBARS). At a concentration of 10(-5) M, estrogens strongly protected against LDL oxidation by 0.5 microM Cu2+ in the following order of inhibition: estradiol (E2) (75%), estrone (E1) (35%) and estriol (E3) (30%). However, the corresponding metabolites of these estrogens, the catechol estrogens, had an even more protective effect on LDL oxidation by 0.5 microM Cu2+ in the following order of inhibition: 2-hydroxyestradiol (2-OHE2) (98%), 2-OHE1 (97%) and 2-OHE3 (96%). E2 and 2-OHE2 from 10(-7) M to 10(-5) M inhibited LDL oxidation in a dose-dependent manner, with a more marked effect for oxidation by 0.1 microM Cu2+ than by 0.5 microM Cu2+. 10(-5) M dexamethasone produced a slight (10%) but significant inhibition of LDL oxidation by 0.5 microM Cu2+. In addition, the estrogens and catechol estrogens were also effective in protecting against HDL oxidation by 0.5 microM Cu2+. Other steroids including DHEA and DHEA-sulfate had no antioxidative effects on either LDL or HDL in this system. These results indicate that estrogens and their metabolites, the catechol estrogens, exert antioxidative effects on both LDL and HDL. The catechol estrogens may be more important antioxidants than estrogens for both LDL and HDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidants↗
PubMedDate not supplied

Herbicidal potential of catechol as an allelochemical.

Catechol is an allelochemical which belongs to phenolic compounds synthesized in plants. Its herbicidal effects on weed species; field poppy (Papaver rhoeas), creeping thistle (Cirsium arvense), henbit (Lamium amplexicaule) and wild mustard (Sinapis arvensis) were investigated using wheat (Triticum vulgare) and barley (Hordeum vulgare) species as control plants. In comparison to 2,4-D (a common synthetic herbicide), 13.64 mM of catechol have been found to have a strong herbicidal effect, as effective as 2,4-D on field poppy weed by killing it, and a suppressive herbicidal effect on the other weeds by inhibiting their growth significantly. Concerning all the weeds, in general, elongation of the shoot was affected more negatively than that of the root. Fresh weights of the weeds were decreased by catechol significantly only in field poppy but not in other weeds. The study reveals that catechol is a potent inhibitor of growth of the weeds and therefore it can be evaluated as a herbicide for future weed management strategies.

2,4-Dichlorophenoxyacetic Acid↗
PubMedDate not supplied

Electrophysiological comparison between catechol- and urea-induced myoclonus models in the rat.

Catechol- and urea-induced myoclonus models in the rat were electrophysiologically compared to clarify pathophysiological differences. Catechol-induced myoclonus had various similarities with cortical reflex myoclonus in that there were electroencephalogram (EEG) discharges prior to myoclonic discharges, a spread of myoclonic discharges from the rostral to the caudal site, and a high amplitude somatosensory evoked potential (SEP). In urea-induced myoclonus, there were no EEG discharges related to myoclonic discharges and no enlarged SEP components as in reticular reflex myoclonus. Catechol-induced myoclonus had two evoked EMG responses of the biceps femoris at mean onsets of 8.0(C1) and 13.4 (C2) ms, and urea-induced myoclonus had a response (U1) at the mean onset of 10.2 ms. A study of the effects of various lesions in the central nervous system on these evoked EMG responses suggests that C1 is a monosynaptic spinal reflex. C2 which disappeared when the bilateral sensorimotor cortex for the hind limb had been resected and the lesion cooled is generated by the deep cerebral structures, such as the thalamus or basal ganglia, and U1 originates in the brain stem reticular formation. These results imply definitive differences of the pathophysiological mechanisms between catechol- and urea-induced myoclonus.

Animals↗
PubMed1978

Studies on rheomelanins. V. Hemolysis associated with the transformation of catechol into rheomelanin in human blood.

Incubation of 2 mg amounts of catechol in 5 ml samples of heparinated blood plasma from four subjects at 38 degrees C for 24 h produced plasma-soluble rheomelanins. These solutions had the brown color and the yellow-green fluorescence in ultraviolet light of 366 nm of other rheomelanins. Their differential ultraviolet and visible spectra showed a rheomelanin absorption maximum at 344 nm. Paper chromatograms of the rheomelanin-plasma solutions in 5% methanol-95% water showed elongated spots of rheomelanins with RF values of 0.82, on Whatman No. 1 paper. Using heparinated distilled water adjusted to pH 7.4 with sodium bicarbonate instead of human blood plasma gave markedly different findings from those obtained with the plasma rheomelanin solutions. Incubation of 4 mg amounts of catechol in 10 ml samples of heparinated whole blood from four subjects for 24, 32 and 48 at 38 degrees C produced rheomelanins as found in the plasma separated from the blood after incubation. The differential ultraviolet and visible spectra of these solutions revealed hemolysis caused by the catechol rheomelanins; this was more marked with longer incubations. The hemolysis was manifested by two absorption peaks at about 270 and 400 nm. Paper chromatography revealed the brown elongated spots of catechol rheomelanins with an RF value of 0.82. Other spots owing to the products of hemolysis were also present.

Catechols↗
PubMed1986

Estrogens with reduced catechol-forming capacity fail to induce implantation in the rat.

Catechol estradiol can induce implantation of the embryo in a progesterone-primed uterus, but we do not know whether conversion of estrogen to a catechol is essential for implantation. The present study examined the ability of fluorinated estradiols that have a reduced capability of catechol formation to induce implantation. Delayed implantation in rats that were hypophysectomized on the third day postcoitum was maintained by daily injection of progesterone. On the fifth day of progesterone treatment they were injected intravenously with estradiol-17 beta (E2), or various doses of 2-fluoroestradiol-17 beta (2-F1-E2) or 4-fluoroestradiol-17 beta (4-F1-E2) and examined 24 hr later for evidence of initiation of implantation. All animals treated with 25 ng of E2 showed normal numbers of implantation sites, as did those receiving 60 ng of 4-F1-E2. In contrast, 2-F1-E2 failed to initiate implantation with doses as high as 300 ng per animal; there were only single sites in two of eight rats treated with 500 ng. Initiation of implantation was not correlated with lack of uterotropic estrogenicity. The results suggest that formation of catechol estrogen may be an important step in mediating estrogen function for implantation of the embryo.

Animals↗
PubMed1975

Extradiol cleavage of 3-substituted catechols by an intradiol dioxygenase, pyrocatechase, from a Pseudomonad.

Pyrocatechase (catechol 1,2-oxidoreductase (decyclizing), EC 1.13.11.1), a ferric ion-containing dioxygenase from Pseudomonas arvilla C-1, catalyzes the intradiol cleavage of catechol with insertion of 2 atoms of molecular oxygen to form cis,cis-muconic acid. The enzyme also catalyzed the oxidation of various catechol derivatives, including 4-methylcatechol, 4-chlorocatechol, 4-formylcatechol (protocatechualdehyde), 4,5-dichlorocatechol, 3,5-dichlorocatechol, 3-methylcatechol, 3-methoxycatechol, and 3-hydroxycatechol (pyrogallol). All of these substrates gave products having an absorption maximum at around 260 nm, which is characteristic of cis,cis-muconic acid derivatives. However, when 3-methylcatechol was used as substrate, the product formed showed two absorption maxima at 390 and 260 nm. These two absorption maxima were found to be attributable to two different products, 2-hydroxy-6-oxo-2,4-heptadienoic acid and 5-carboxy-2-methyl-2,4-pentadienoic acid (2-methylmuconic acid). The former was produced by the extradiol cleavage between the carbon atom carrying the hydroxyl group and the carbon atom carrying the hydroxyl group and the carbon atom carrying the methyl group; the latter by an intradiol cleavage between two hydroxyl groups. Since these products were unstable, they were converted to and identified as 6-methylpyridine-2-carboxylic acid and 2-methylmuconic acid dimethylester, respectively. Similarly, 3-methoxycatechol gave two products, namely, 2-hydroxy-5-methoxycarbonyl-2,4-pentadienoic acid and 5-carboxy-2-methoxy-2,4-pentadienoic acid (2-methoxymuconic acid). With 3-methylcatechol as substrate, the ratio of intradiol and extradiol cleavage activities of Pseudomonas pyrocatechase during purification was almost constant and was about 17. The final preparation of the enzyme was homogeneous when examined by disc gel electrophoresis and catalyzed both reactions simultaneously with the same ratio as during purification. All attempts to resolve the enzyme into two components with separate activities, including inactivation of the enzyme with urea or heat, treatment with sulfhydryl-blocking reagents or chelating agents, and inhibition of the enzyme with various inhibitors, proved unsuccessful. These results strongly suggest that Pseudomonas pyrocatechase is a single enzyme, which catalyzes simultaneously both intradiol and extradiol cleavages of some 3-substituted catechols.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1989

Catechol and indole metabolism in rostral ventrolateral medulla change synchronously with changing blood pressure.

Catechol and indole metabolism in rostral ventrolateral medulla (RVLM or C1) was studied in response to changes in blood pressure across different rat strains. Sprague-Dawley, Wistar Kyoto normotensive and spontaneously hypertensive rats were anesthetized with urethane and had a 250 mu carbon paste in vivo electrochemical electrode implanted in RVLM area. Two electrochemical peaks were detected in this region. The first was at 0.12 V and the second at 0.28 V. To identify the electrochemical peaks, inhibitors of monoamine metabolism were administrated. alpha-Methylparatyrosine (tyrosine hydroxylase inhibitor), fusaric acid (dopamine-beta-hydroxylase inhibitor), pargyline (monoamine oxidase inhibitor) and LY 134046 (phenylethanolamine-N-methyltransferase inhibitor) showed that the first peak measured in the RVLM is likely to have multiple components including epinephrine, norepinephrine and 3,4-dihydroxyphenylacetic acid. The second peak most likely represents 5-hydroxyindole acetic acid. Phenylephrine or nitroprusside was infused to increase or decrease the blood pressure. Phenylephrine-induced hypertension reduced the catechol peak and increased the indole peak. By contrast, nitroprusside-induced hypotension produced reciprocal results. Hypotension led to an increase in the catechol peak and a reduction in the indole peak. The same pattern was observed in all three rat strains. We conclude that catechol and serotonin metabolism in RVLM changes in close relation to changes in blood pressure.

Animals↗
PubMed1984

Chloridazon-catechol dioxygenases, a distinct group of meta-cleaving enzymes.

We previously described a new meta-cleaving enzyme, termed chloridazon-catechol dioxygenase. The present paper describes the comparison of this enzyme with the meta-cleaving enzymes of eighteen strains of soil bacteria isolated with various aromatic compounds. Four of these strains were isolated with the herbicide chloridazon, six with the analgeticum aminopyrine and one with the analgeticum antipyrine as sole carbon source. These strains all belonged to a new type of bacteria, called Phenylobacteria. The seven other strains were isolated with aromatic compounds such as toluene, 3-phenylpropionate, benzoate, papaverine and 4-chlorobenzoate, and belonged to various species including Pseudomonas, Acinetobacter and Nocardia. In double diffusion experiments with antibodies, prepared against chloridazon-catechol dioxygenase, extracts from the eleven strains of Phenylobacteria gave a cross reaction, whereas the extracts of the seven other strains showed no reaction. The enzymes of the eleven positive strains showed the same characteristic kinetic behaviour as the previously described enzyme. In contrast to catechol 2, 3-dioxygenase they needed the addition of exogenous Fe2+ ions for activity. On ion-exchange chromatography they emerged at the same buffer concentration as chloridazon-catechol dioxygenase. In polyacrylamide electrophoresis they migrated identically. The linkage map derived from the activities of the various enzymes with 10 different substrates revealed an identity of more than 80% for these eleven enzymes. So the meta-cleaving enzymes of the Phenylobacteria seem to form a distinct group among the non-heme iron-containing dioxygenases.

Antibody Specificity↗
PubMed1982

Chemical cocarcinogenesis with the use of a subclone derived from Balb/3T3 cells with catechol as cocarcinogen.

This study was performed for the detection of cocarcinogens by transformation in vitro with the use of a subclone of a Balb/3T3 cell line. Dose response, cytotoxicity, and transformation studies were done with the use of an indirect-acting carcinogen, benzo[a]pyrene (B[a]P), a direct-acting alkylating carcinogen, beta-propiolactone (BPL), and the mouse skin cocarcinogen catechol. The rate of transformation was notably higher in groups treated with B[a]P and catechol or BPL and catechol than in groups treated with either B[a]P or BPL. Catechol alone did not induce any transformation. All the cells isolated from the transformed foci showed characteristics of malignantly transformed cells, such as anchorage-independent growth. Thus chemical cocarcinogenesis was accomplished in vitro similar to that accomplished in in vivo studies reported earlier on mouse skin.

Animals↗
PubMed1993

Effects of sodium nitrite and catechol, 3-methoxycatechol, or butylated hydroxyanisole in combination in a rat multiorgan carcinogenesis model.

Effects of simultaneous treatment with NaNO2 and butylated hydroxyanisole, catechol, or 3-methoxycatechol were examined in a rat multiorgan carcinogenesis model. Groups of 15 animals were given a single i.p. injection of 100 mg/kg of body weight diethylnitrosamine, 4 i.p. injections of 20 mg/kg of body weight N-methylnitrosourea, 4 s.c. injections of 40 mg/kg of body weight dimethylhydrazine, p.o. treatment with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for the first 2 weeks and p.o. treatment with 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine in the drinking water for the next 2 weeks of the initial 4-week initiation period. Starting 3 days after the completion of these carcinogen treatments, animals were given diets containing 2% butylated hydroxyanisole, 0.8% catechol, 2% 3-methoxycatechol, or basal diet either alone or in combination with 0.3% sodium nitrite until week 28, when complete autopsy was performed. Histological examination showed that NaNO2 strongly enhanced development of forestomach lesions but inhibited that of glandular stomach lesions in rats simultaneously given catechol or 3-methoxycatechol with or without prior carcinogen exposure. 3-Methoxycatechol promoted esophageal carcinogenesis either with or without NaNO2, but promoting effects of catechol were evident only in the presence of NaNO2. In addition, treatment with NaNO2 after carcinogen exposure enhanced forestomach carcinogenesis. These results indicate that NaNO2 can modify phenolic antioxidant-induced cell proliferation and/or carcinogenesis, particularly in the upper digestive tract.

Animals↗
PubMed1993

Relative abundance and the relationships between aniline, phenol and catechol degraders in fresh water.

Relative abundance and relationships between aniline, phenol and catechol degraders were investigated in unpolluted and polluted fresh waters in Osaka prefecture, Japan. Phenol and catechol degraders were found more frequently compared to aniline degraders. The results indicate that these degraders were more abundant in polluted waters than in unpolluted waters. Aniline degraders isolated from the Ina River water showed a higher capability of degrading catechol than phenol. Analysis on sequence homology among these three kinds of degraders indicated a possible relationship between aniline degraders and certain strains of both catechol and phenol degraders.

Alcaligenes↗
PubMed2003

A structure-activity relationship study of catechol-O-methyltransferase inhibitors combining molecular docking and 3D QSAR methods.

A panel of 92 catechol-O-methyltransferase (COMT) inhibitors was used to examine the molecular interactions affecting their biological activity. COMT inhibitors are used as therapeutic agents in the treatment of Parkinson's disease, but there are limitations in the currently marketed compounds due to adverse side effects. This study combined molecular docking methods with three-dimensional structure-activity relationships (3D QSAR) to analyse possible interactions between COMT and its inhibitors, and to incite the design of new inhibitors. Comparative molecular field analysis (CoMFA) and GRID/GOLPE models were made by using bioactive conformations from docking experiments, which yielded q2 values of 0.594 and 0.636, respectively. The docking results, the COMT X-ray structure, and the 3D QSAR models are in agreement with each other. The models suggest that an interaction between the inhibitor's catechol oxygens and the Mg2+ ion in the COMT active site is important. Both hydrogen bonding with Lys144, Asn170 and Glu199, and hydrophobic contacts with Trp38, Pro174 and Leu198 influence inhibitor binding. Docking suggests that a large R1 substituent of the catechol ring can form hydrophobic contacts with side chains of Val173, Leu198, Met201 and Val203 on the COMT surface. Our models propose that increasing steric volume of e.g. the diethylamine tail of entacapone is favourable for COMT inhibitory activity.

Animals↗
PubMed1992

Kinetic and inhibition studies on catechol-O-methyltransferase affinity labelling by N-(3,4-dihydroxyphenyl)maleimide.

Initial velocity and product inhibition studies have been performed on soluble catechol-O-methyltransferase which has been partially purified from pig liver. The results are consistent with an ordered reaction mechanism, in which S-adenosyl-L-methionine (AdoMet) is the leading substrate. The enzyme is irreversibly inhibited by maleimide derivatives in a biphasic manner, which suggests a differential reaction with two thiol groups. N-(3,4-Dihydroxyphenyl)maleimide, which has a reactive moiety (maleimide ring) and an affinity moiety (catechol ring), acts as an affinity labelling compound on the more reactive SH group; AdoMet and Mg2+ protect against this modification. Total protection of this SH group results in a pseudo-first-order inhibition of the enzyme, with the apparent rate constant being proportional to the inhibitor concentration. All the other maleimide derivatives studied inhibited the enzyme by reacting with one of the two SH groups in a non-specific manner. The reaction of the other, more reactive, SH group was either specific (active-site-directed) or non-specific, depending on the substituent present in the affinity moiety and also on the length of an intermediate chain of methylene groups present between this moiety and the reactive maleimide ring. In the presence of both AdoMet and Mg2+, 3,5-dinitrocatechol, a reversible inhibitor of the enzyme which is competitive with respect to the catechol substrate, protects the enzyme from inactivation by any of the maleimide derivatives. The adducts of these maleimide derivatives formed with dithiothreitol inhibit the enzyme reversibly, showing inhibition patterns that are consistent with the mechanism deduced from the initial velocity and product inhibition studies.

Affinity Labels↗
PubMed2003

Molecular modeling and metabolic studies of the interaction of catechol-O-methyltransferase and a new nitrocatechol inhibitor.

Catechol-O-methyltransferase (COMT, EC 2.1.1.6) plays a central role in the metabolic inactivation of neurotransmitters and neuroactive xenobiotics possessing a catechol motif. 1-(3,4-Dihydroxy-5-nitrophenyl)-2-phenyl-ethanone (BIA 3-202) is a novel nitrocatechol-type inhibitor of COMT, the potential clinical benefit of which is currently being evaluated in the treatment of Parkinson's disease. In the present work we characterize the molecular interactions of BIA 3-202 within the active site of COMT and discuss their implication on the regioselectivity of metabolic O-methylation. Unrestrained flexible-docking simulations suggest that the solution structure of this complex is better described as an ensemble of alternative binding modes, in contrast to the well defined bound configuration revealed by the X-ray structures of related nitrocatechol inhibitors, co-crystallized with COMT. The docking results wherein presented are well supported by experimental evidence, where the pattern of in vitro enzymatic O-methylation and O-demethylation reactions are analyzed. We propose a plausible explanation for the paradoxical in vivo regioselectivity of O-methylation of BIA 3-202, as well as of its related COMT inhibitor tolcapone. Both compounds undergo in vivo O-methylation by COMT at either meta or para catechol hydroxyl groups. However, results herein presented suggest that, in a subsequent step, the p-O-methyl derivatives are selectively demethylated by a microsomal enzyme system. The overall balance is the accumulation of the m-O-methylated metabolites over the para-regioisomers. The implications for the general recognition of nitrocatechol-type inhibitors by COMT and the regioselectivity of their metabolic O-methylation are discussed.

Acetophenones↗
PubMed2006

Comparative study of ortho- and meta-nitrated inhibitors of catechol-O-methyltransferase: interactions with the active site and regioselectivity of O-methylation.

In this work, we present a comparative case study of "ortho-" and "meta-nitrated" catecholic inhibitors of catechol-O-methyltransferase (COMT), with regard to their interaction with the catalytic site of the enzyme and the in vitro regioselective formation of their mono-O-methyl ether metabolites. In particular, the effects of altering the attachment position of the inhibitors' side-chain substituent, within the classic nitrocatechol pharmacophore, were investigated. For this purpose, we compared two simple regioisomeric nitrocatechol-type inhibitors of COMT, BIA 3-228 and BIA 8-176, which contain the benzoyl substituent attached at the meta and ortho positions, respectively, relative to the nitro group. The two compounds were slowly O-methylated by COMT in vitro, but the particular substitution pattern of each compound was shown to have a profound impact on the regioselectivity of their O-methylation. To provide a plausible interpretation of these results, a comprehensive analysis of the protein-inhibitor interactions and of the relative chemical susceptibility to O-methylation of the catechol hydroxyl groups was performed by means of docking simulations and ab initio molecular orbital calculations. The major structural and chemical factors that determine the enzyme regioselectivity of O-methylation were identified, and the X-ray structure of the complex of COMT with S-adenosyl-l-methionine and BIA 8-176 is herein disclosed. This is the first reported structure of the soluble form of COMT complexed with a nitrocatecholic inhibitor having a bulky substituent group in adjacent position (ortho) to the nitro group. Structural and dynamic aspects of this complex are analyzed and discussed, in the context of the present study.

Animals↗