Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Benzophenones”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,171 records · Page 65Linked to original sources
PubMed2002

18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson's disease.

Tolcapone is a potent, selective, and reversible inhibitor of cathecol-O-methyl-transferase (COMT). This enzyme plays a crucial role in the extraneural inactivation of catecholamine neurotransmitters. Tolcapone's ability to inhibit central COMT in humans at therapeutic concentrations is not yet clear. The aim was to determine the effect of tolcapone on central COMT activity in Parkinson's disease (PD) using (18)F-dopa positron emission tomography (PET). The study was a randomized two-way crossover study. Twelve PD patients were recruited. On the treatment days patients were given either tolcapone (200 mg) or placebo together with levodopa/carbidopa (100/125 mg) 1 h before the injection of (18)F-dopa. Data were acquired in 25 frames over 94 min for the first PET scan period. At the end of this period the patients were removed from the scanner for 90 min and subsequently repositioned and data acquired in six 10-min time frames over 60 min. Influx constants (Ki) were computed using a graphical approach with a plasma input function. Mean (18)F-dopa putamen Ki's for the first 30-90 min, primarily reflecting central dopa decarboxylase (DDC) activity, were similar in PD patients whether tolcapone was present (0.0078 +/- 0.0031 min(-1)) or absent (0.0078 +/- 0.0030 min(-1)). Mean putamen Ki values calculated 180-240 min after injection of (18)F-dopa, reflecting both central DDC and COMT activity, were unchanged from 30-90' values in the presence of tolcapone (0.0079 +/- 0.0030), implying blockade of central COMT, but were significantly reduced (0.0059 +/- 0.0028) in the absence of this drug. These findings are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD.

Aged↗
PubMed2002

Structure-activity relationships for gene activation oestrogenicity: evaluation of a diverse set of aromatic chemicals.

Structure-activity relationships for oestrogenicity were developed based on 120 aromatic chemicals evaluated in the Saccharomyces cerevisiae-based Lac-Z reporter assay. Relative gene activation was compared to 17 beta-estradiol and varied over eight orders of magnitude. Analysis of the data compared to 17 beta-estradiol identified three structural criteria that were related to xenoestrogen activity and potency: (1) the hydrogen-bonding ability of the phenolic ring mimicking the A-ring, (2) a hydrophobic centre similar in size and shape to the B- and C-rings, and (3) a hydrogen-bond donor mimicking the 17 beta-hydroxyl moiety of the D-ring, especially with an oxygen-to-oxygen distance similar to that between the 3- and 17 beta-hydroxyl groups of 17 beta-estradiol. Binding data were segregated into activity clusters including strong, moderate, weak, and detectable gene expression, and those compounds that were inactive. The hydrogen-bonding ability of hydroxy group in the 3-position on 17 beta-estradiol was observed to be essential for gene activation. Compounds with a 4-hydroxyl substituted benzene ring and a hydrophobic moiety of size and shape equivalent to the B-ring of 17 beta-estradiol were generally observed to be weakly active compounds. Moderately active compounds have a 4-hydroxyl substituted benzene ring with a hydrophobic moiety equivalent in size and shape to the B- and C-ring of 17 beta-estradiol, or have a high hydrogen-bond donor capacity owing to the presence of halogens on a nonphenolic ring. Strongly active compounds, similar to 4,4'-diethylethylene bisphenol (DES), possess the same hydrophobic ring structure as described for moderately active compounds and an additional hydroxyl group with an oxygen-to-oxygen distance close to that exhibited by the 3- and 17-hydroxyl groups of 17 beta-estradiol.

Benzophenones↗
PubMed2000

Simultaneous detection of ubiquinol-10, ubiquinone-10, and tocopherols in human plasma microsamples and macrosamples as a marker of oxidative damage in neonates and infants.

A HPLC-method was developed for the simultaneous detection of the lipophilic antioxidants ubiquinol-10, ubiquinone-10, alpha-tocopherol, and gamma-tocopherol in plasma macrosamples (100 microl) as well as microsamples (10 microl) using electrochemical detection with internal standardization (gamma-tocotrienol, ubiquinol-9, ubiquinone-9). The use of a mobile phase containing ammonium formate instead of lithium perchlorate as conductivity salt and the use of a PEEK column instead of a steel column improved the reproducibility of the method. The components were separated on a RP C18 column. The detection limits for all components were between 1 and 28 fmol. The within-day precision varied between 3 and 13% for all measured substances. The analytical recovery was between 93 and 109%. The plasma levels from 10 healthy donors were determined in microsamples and macrosamples taken by micropuncture or venous puncture, respectively. A good correlation of the antioxidant levels for both methods strengthened the reliability and the transferability of the results. The present method can be used to assess the role of these antioxidants in diseases associated with oxidative damage in childhood.

Antioxidants↗
PubMed1993

Human monocytes respond to leukotriene B4 with a transient increase in cytosolic calcium.

To define the intracellular activation events stimulated by leukotriene B4 (LTB4) in human monocytes, we investigated the transient increase in cytosolic free calcium levels ([Ca2+]i) elicited by this lipid mediator. Using elutriated human monocytes, LTB4 caused a dose-dependent increase in [Ca2+]i with an ED50 of 1.0 nM. The LTB4-induced [Ca2+]i response exhibited ligand selectivity, with both the diastereomer 5S-12S-diHETE and the 20-COOH LTB4 inactive at 500 nM, while 20-OH LTB4 was a partial agonist with an approximate ED50 of 10 nM. This response demonstrated stimulus-specific deactivation and was inhibited by the specific LTB4 receptor antagonist LY-223982. These results suggest that LTB4 stimulated an increase in [Ca2+]i via interaction with a defined LTB4 receptor. The inhibitory effects of pertussis toxin and PMA on the LTB4-induced [Ca2+]i suggest that a receptor-linked guanine nucleotide-binding protein and protein kinase C are involved in the regulation of the LTB4-elicited increase in [Ca2+]i. The LTB4-induced cell activation event may play a key role in the functional responses elicited by LTB4 in human monocytes.

Benzophenones↗
PubMed2002

Superoxide anion-dependent Raf/MEK/ERK activation by peroxisome proliferator activated receptor gamma agonists 15-deoxy-delta(12,14)-prostaglandin J(2), ciglitazone, and GW1929.

In this study, we examined the signaling pathways for extracellular signal-related protein kinase (ERK) activation by three structurally different peroxisome proliferator activated receptor-gamma (PPARgamma) agonists. In murine C2C12 myoblasts, treatment with 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), ciglitazone, and GW1929 leads to ERK1/2 phosphorylation in a time- and concentration-dependent manner. Consistent with ERK phosphorylation, mitogen activated protein/ERK kinase (MEK) phosphorylation as well as Raf-1 kinase activity are also accordingly stimulated, while the constitutive Ser259 phosphorylation of Raf-1 is decreased. The ERK phosphorylation induced by PPARgamma agonists is not blocked by the PKC inhibitors GF109203X and Ro31-8220, the PI3K inhibitor wortmannin, the Ras inhibitor FPTI, the negative mutant of Ras, or the PPARgamma antagonist bisphenol A diglycidil ether. Expression of PPARgamma2 without DNA binding domain or with a nonphosphorylatable mutant (S112A) fails to change ERK phosphorylation by 15d-PGJ(2). On the contrary, the ERK phosphorylation by PPARgamma agonists is inhibited by the MEK inhibitor PD98059, GSH, and permeable SOD mimetic MnTBAP. Chemiluminescence study reveals that these three PPARgamma agonists are able to induce superoxide anion production, with an efficacy similar to their action on ERK phosphorylation. Consistent with this notion, we also show that superoxide anion donor 2,3-dimethoxy-1,4-naphoquinone elicits ERK phosphorylation. In this study, we for the first time demonstrate a novel mechanism, independent of Ras activation but initiated by superoxide anion production, for PPARgamma agonists to trigger the Raf-MEK-ERK1/2 signaling pathway.

Animals↗
PubMed1993

Assessment of the reproductive toxic potential of dermally applied 2-hydroxy-4-methoxybenzophenone to male B6C3F1 mice.

The potential of 2-hydroxy-4-methoxybenzophenone (HMB) to cause male reproductive toxicity was assessed in B6C3F1 mice. HMB was administered topically for 13 weeks (5 days/week) to groups of 10 mice each at dosages of 0, 10, 20, 100, or 400 mg/kg/day. Additional high dosage and control mice were also included and euthanized at interim time points to characterize the time course of any effects. After 91 days (or at interim periods) mice were euthanized and reproductive organ weights, cauda epididymal sperm concentration and proportion of motile and abnormal sperm, and testicular spermatid concentration were determined. Testicular histology was evaluated in fixed tissue. HMB treatment had no effect on body weight gain or any of the male reproductive parameters assessed at any time point. These results indicate that topically applied HMB has no reproductive toxic potential in male B6C3F1 mice at dosages as high as 400 mg/kg/day.

Administration, Topical↗
PubMed1999

Site-specific derivatization of RNA with photocrosslinkable groups.

Derivatization of RNA with heterobifunctional photocrosslinking reagents becomes an increasingly popular method for the analysis of structural properties of ribonucleoprotein complexes. This article describes a simple chemical modification-derivatization strategy used to introduce selected chemical groups at specific internal positions within the RNA ribose backbone. The strategy is based on the coupling of a haloacetyl adduct to a thiol residue in the phosphodiester bond. The use of a number of RNA probes derivatized with several different photoreactive groups can provide invaluable information on the structural distribution of components in complex ribonucleoprotein assemblies.

Azides↗
PubMed2001

Structure toxicity relationships--how useful are they in predicting toxicities of new drugs?

This chapter provides just a few newer examples of structural moieties found in drugs that have been associated with reactive metabolite formation and toxicities. For a discussion of several other structures in drugs that undergo metabolic activation to reactive intermediates, the reader is directed to previous volumes in this series and other chapters in this book, as well as a previous condensed review (Nelson, 1982). Since that review, some new knowledge allows us to better predict that some structural moieties are more likely than others to form drug reactive metabolites that may be involved in causing toxic effects in humans. For example, most aniline-, thiophene-, and nitroaromatic-containing drugs have had a relatively high incidence of adverse effects, and it would be prudent in the drug discovery process to avoid these substructures if possible. However, as illustrated by the case of olanzapine, these structures may be important for potent activity, and could therefore be beneficial in some cases. The glitazones represent a new class of drugs with a unique thiazolidinedione structure. This raises two important points. First, it demonstrates how limited our knowledge base is in regard to structure toxicity relationships when new structures are introduced. Our approaches must be very empirical and are far from quantitative for the reasons outlined in the introduction. Secondly, the glitazones point out the importance of benefit/risk considerations. This was a new structural class of drugs with a unique spectrum of action that is very beneficial in the treatment of a major disease. Despite some suspected risk of toxicity, based on early trials, troglitazone was approved for use with careful monitoring. This author believes that was the right decision, as was the decision to withdraw the drug when the risk became unacceptable, especially with the introduction of safer alternatives. If this were just another NSAID (e.g., bromfenac), there would be little reason for approval. In summary, as I pointed out previously (Nelson, 1982), with our limited knowledge of structure toxicity relationships, we can only make reasonable judgments as to risk assessment of a new drug in humans, and hope that we neither release a dangerous chemical entity nor, as importantly, abort an effective one.

Analgesics↗
PubMed1998

A cell culture model of cerebral ischemia as a convenient system to screen for neuroprotective drugs.

Aggregation cultures of rat brain were exposed to a combination of anoxia and hypoglycaemia for 30 minutes. Thereafter, the release of lactate dehydrogenase into the cell culture medium was monitored up to 4 days as a measure of cell damage after the ischemic insult. Some cultures were treated with different concentrations of deprenyl or tolcapone, selective inhibitors of monoamine oxidase B and catechol-O-methyltransferase, respectively. After 1 day in culture, the release of lactate dehydrogenase was significantly reduced in cultures treated with deprenyl (at 1 nM. 100 nM, and 10 microM), as well as in cultures treated with 1 nM or 100 nM tolcapone; 10 microM of tolcapone, on the other hand, resulted in a toxic effect on the cell aggregates. No differences in the release of lactate dehydrogenase into the medium was observed in the aggregates treated with drugs as compared with the control cultures after 2 or 4 days post-ischemia.

Animals↗
PubMed1990

Ro 40-7592: inhibition of COMT in rat brain and extracerebral tissues.

A random biochemical screening followed by lead optimization culminated in the discovery of Ro 40-7592 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone). Ro 40-7592 was found to inhibit COMT in a competitive fashion both in the CNS and in the periphery (Ki for the liver enzyme = 30 nM). Ro 40-7592 (30 mg/kg p.o.) combined with benserazide (15 mg/kg p.o.) and a low dose of L-DOPA (10 mg/kg p.o.) almost completely blocked (for about 6 h) the formation of 3-O-methyldopa (3-OMD) in brain and plasma, producing a long-lasting increase of L-DOPA in plasma and a parallel marked increase of L-DOPA and dopamine in the brain. Ro 40-7592, combined with peripheral decarboxylase inhibitors and L-DOPA (as in Madopar and Sinemet), will offer substantial advantages in the therapy of Parkinson's disease, i.e. enhanced bioavailability and prolonged plasma half-life of L-DOPA, pronounced DOPA sparing effect and blockade of 3-OMD formation.

Animals↗
PubMed1994

Role of monoamine oxidase and catechol-O-methyltransferase in the metabolism of renal dopamine.

Incubation of slices of rat renal cortex with 50 microM L-DOPA during 15 min resulted in the formation of dopamine and of its deaminated (3,4-dihydroxyphenylacetic acid; DOPAC), methylated (3-methoxytyramine; 3-MT) and deaminated plus methylated (homovanillic acid; HVA) metabolites. The presence of pargyline (100 microM) resulted in a 90% reduction in the formation of DOPAC and HVA; levels of dopamine and 3-MT were found to be significantly increased. A concentration dependent decrease in the formation of methylated metabolites was obtained in the presence of (10, 50 and 100 microM) tropolone (10-50% reduction) and (0.1, 0.5, 1.0 and 5.0 microM) Ro 40-7592 (50-95% reduction). Ro 40-7592 was also found to significantly increase DOPAC (20-40%) and dopamine (10-30%) levels, whereas tropolone slightly increased DOPAC (10%) levels. These results show that deamination represents the major pathway in the metabolism of newly formed dopamine under in vitro experimental conditions in the rat kidney. In addition, only when MAO is inhibited does methylation appear to represent an alternative metabolic pathway.

Animals↗
PubMed1996

The contribution by monoamine oxidase and catechol-O-methyltransferase to the total-body and pulmonary plasma clearance of catecholamines.

To study the effects of inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) on the removal of circulating catecholamines, anaesthetized rabbits were infused for 120 min with 3H-labelled noradrenaline, adrenaline and dopamine. Total-body plasma clearances (Cltot) and pulmonary fractional extractions (ERp) of the infused amines and the cardiac output of plasma (CO(p)) were determined under steady-state conditions at the end of each of two consecutive 60-min treatment periods. MAO and COMT were inhibited by treatment with pargyline (40 mg/kg) and tolcapone (3 mg/kg followed by 1.5 mg/kg given every 30 min), respectively. Two groups of animals were studied. Group I involved animals treated with tolcapone throughout and given pargyline at the beginning of the second treatment period. In group II, pargyline was given at the beginning of the first, and the treatment with tolcapone was started at the beginning of the second treatment period. As previous experiments had shown that COMT inhibition alone is without any effect on Cltot of the three catecholamines considered here, the results obtained in the first treatment period of group I can be taken to reflect control results. At the end of the first treatment period, Cltot of noradrenaline, adrenaline and dopamine (expressed as a percentage of CO(p)) was 88%, 85% and 142%, respectively, in group I (COMT inhibition) and 67%, 77% and 115%, respectively, in group II (MAO inhibition; P < 0.05 for the group difference regarding Cltot of noradrenaline and dopamine). MAO inhibition on top of COMT inhibition (group I) lowered Cltot of noradrenaline, adrenaline and dopamine by 23%, 12% and 26%, respectively, and COMT inhibition on top of MAO inhibition (group II) reduced Cltot of these catecholamines by 13%, 20% and 17%, respectively. At the end of the first treatment period, the pulmonary plasma clearance (Clp = ERp x CO(p)) of noradrenaline and dopamine was 13 and 25 ml kg-1 min-1, respectively, in group I and 12 and 28 ml kg-1 min-1, respectively, in group II. Clp of adrenaline did not differ from zero in either group. Clp of noradrenaline and dopamine was reduced by 74% and 70%, respectively, when both enzymes were inhibited in group I and by 70% and 67%, respectively, when both enzymes were inhibited in group II. Hence, inhibition of either MAO or COMT alone had little, if any, effect on the removal of noradrenaline, adrenaline and dopamine on passage through the systemic and pulmonary circulation. Combined inhibition of both MAO and COMT was highly effective in reducing the pulmonary clearance of noradrenaline and dopamine, but produced only minor decreases in the total-body clearance of all three catecholamines.

Animals↗
PubMed1993

The part played by catechol-O-methyltransferase in the plasma kinetics of 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylalanine in the anaesthetized rabbit.

The present study, carried out in anaesthetized rabbits, aimed at determining the effects of catechol-O-methytransferase (COMT) inhibition on the plasma kinetics of infused 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxyphenylalanine (DOPA) as well as on endogenous plasma noradrenaline, DOPEG, DOPA and 3-methoxy-4-hydroxyphenylglycol (MOPEG). The plasma kinetics of infused MOPEG were also evaluated. To block the function of COMT, 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592) was given intravenously. Dose-finding experiments, in which the drug-induced fall in endogenous plasma MOPEG was used to quantify COMT inhibition, indicated that a Ro 40-7592 dose of 3 mg/kg followed by 1.5 mg/kg every 30 min was sufficient to obtain a virtually complete inhibition of COMT. More than 150 min of COMT inhibition were required for endogenous MOPEG to disappear from plasma, since the plasma half-life of MOPEG was 54 min. COMT inhibition produced marked increases in the plasma levels of endogenous DOPA (1.7-fold) and DOPEG (3.9-fold) and did not alter endogenous plasma noradrenaline. The results concerning the effect of COMT inhibition on the plasma kinetics of infused DOPA and DOPEG were as follows: the plasma clearance of DOPA was not altered, whereas that of DOPEG fell by 41%; the plasma half-life of DOPA increased from 4.9 to 13.0 min and that of DOPEG from 4.8 to 31.0 min; there was an increase in the volume of distribution of DOPA (2 to 3-fold) and DOPEG (4 to 5-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of catechol-O-methyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit.

The purpose of this study was to elucidate the finding of Friedgen et al. (1993 b) that catechol-O-methyltransferase (COMT) inhibition is much more effective in increasing the plasma concentration of endogenous dihydroxyphenylglycol (DOPEG) than in increasing the plasma concentration of infused DOPEG. To this end, reserpine-pretreated rabbits were anaesthetized and infused with noradrenaline and/or DOPEG, and the plasma clearances of infused noradrenaline (ClNA) and DOPEG (ClDOPEG) as well as the plasma DOPEG response to noradrenaline infusion [as reflected by the ratio of the steady-state increase in plasma DOPEG (delta DOPEG) to that in plasma noradrenaline (delta NA)] were determined before and after blockade of neuronal uptake by desipramine. Experiments were carried out either under control conditions or after COMT inhibition by i.v. administration of 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592). On the assumption that rates of neuronal noradrenaline uptake equal steady-state rates of neuronal DOPEG formation, the desipramine-sensitive components of ClNA and delta DOPEG/delta NA were used to estimate the apparent plasma clearance of DOPEG formed intraneuronally (Clf-DOPEG) in response to noradrenaline infusion. ClNA was 83.6 ml kg-1 min-1 in the absence and 48.1 ml kg-1 min-1 in the presence of desipramine. Neither the former nor the latter value was altered after COMT inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Antagonism by exifone, a new cognitive enhancing agent, of the amnesias induced by four benzodiazepines in mice.

Exifone is a novel compound proposed for treating cognitive decline associated with age and shows corrective effects in animal models of memory dysfunction. The present experiments examined the antagonism by exifone of the amnesias induced in mice in a passive avoidance test by four benzodiazepines: bromazepam, diazepam, lorazepam and triazolam. Subsequent experiments investigated the specificity of exifone's antagonism of benzodiazepine-induced amnesia by examining its interaction with the effects of the benzodiazepines in the staircase test (anxiolytic/sedative activity) and the electroshock test (anticonvulsant activity). The results indicated that exifone clearly antagonised the amnesias induced by the four benzodiazepines, but was without intrinsic effects in the staircase or electroshock test and did not antagonise the effects of the benzodiazepines in these two tests. These results suggest that exifone might be useful for decreasing the amnesias induced by commonly used benzodiazepines without affecting their anxiolytic or anticonvulsant activity.

Amnesia↗