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D R Feller

Publications and source records attributed to D R Feller.

At least 73 records · Page 4Linked to original sources
PubMed1988

Synthesis and thromboxane A2 antagonist activity of N-benzyltrimetoquinol analogues.

It is currently believed that the platelet thromboxane A2 (TXA2/PGH2) receptor is different from the vascular TXA2/PGH2 receptor. While the majority of TXA2 receptor antagonists are structurally related to the prostaglandins, trimetoquinol (TMQ) represents a unique nonprostanoid antagonist. TMQ also possesses beta-adrenergic activity; however, an N-benzyl substituent on TMQ has been shown to impart some selectivity for platelet antiaggregatory activity versus beta-adrenergic activity. In this study, we examined the synthesis and TXA2 antagonist activity of a series of substituted N-benzyl analogues of TMQ. While these analogues showed an apparent direct correlation between platelet antiaggregatory activity and electron-donating ability of the N-benzyl substituents, no such correlation could be demonstrated for the inhibition of contractile responses. Thus, nonprostanoid TXA2 antagonists can be used to demonstrate differences between platelet and vascular TXA2/PGH2 responses.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

Induction of peroxisomal fatty acyl-CoA oxidase and microsomal laurate hydroxylase activities by beclobric acid and two metabolites in primary cultures of rat hepatocytes.

Beclobrate [2-(4-[(4-chlorophenyl)methyl]phenoxy)-2-methylbutyric acid ethyl ester], a structural analog of clofibrate, is used clinically as a lipid-lowering agent. Although, like clofibrate, beclobrate produces a profound hepatomegalic response in rodents, no studies of this drug on hepatic peroxisome proliferation have appeared. We have examined, relative to clofibric acid (CPIB), the concentration-dependent effects of beclobric acid (Beclo), the activity moiety of beclobrate, and two oxidized metabolites [a carbinol (M2) and a benzophenone (M3)] on peroxisomal fatty acyl-CoA oxidase (FACO) and microsomal laurate hydroxylase (LH) activities in primary cultures of rat hepatocytes. All compounds induced FACO and LH activities in a concentration-dependent manner after a 72 hr incubation with the cultured cells. Beclo was 4.8- and 6.5-fold more potent than CPIB as an inducer of FACO and LH respectively. M2 and M3 were more potent than Beclo as inducers of FACO and LH. Additionally, all compounds produced significant elevations relative to untreated control cultures in cellular lactate dehydrogenase activity (1.6- to 2.2-fold). We conclude that (1) Beclo is more potent than CPIB as an inducer of peroxisome proliferation-associated enzyme activities; (2) two metabolites of Beclo are more potent than the parent molecule as inducers of these activities and (3) these metabolites may contribute to the lipid-lowering and/or hepatomegalic effects of beclobrate in rats.

Acyl-CoA Oxidase↗
PubMed1987

Pharmacological evaluation of the beta-adrenoceptor agonist and thromboxane antagonist properties of N-substituted trimetoquinol analogues.

The beta 1- and beta 2-adrenoceptor agonist and U46619 (a thromboxane A2 agonist) antagonist properties of trimetoquinol (TMQ, I) and its optical isomers, and N-substituted TMQ analogues (methyl, II; 2-hydroxyethyl, III; cyclic sulfite N-2-chloroethyl, IV; 2-chloroethyl, V; benzyl, VI) were studied in guinea pig atria and trachea and rat aorta, respectively. All compounds gave concentration-dependent responses in atria and trachea, and the rank order of beta-adrenoceptor agonist potency was I greater than II greater than III greater than IV greater than V greater than VI. Whereas N-substitution reduced potency for beta-agonism, the beta 2/beta 1-selectivity ratio was enhanced by increasing the size of the N-substituent. All analogues possessed equal or greater (up to 41-fold more) beta 2-selectivity than I. Propranolol was a competitive antagonist of selected TMQ analogues in guinea pig trachea and atria, thus confirming the beta-adrenoceptor actions of these drugs. The optical isomers of TMQ gave a rank order of agonist potency of S(-)-TMQ greater than R(+)-TMQ, and a beta 2/beta 1-selectivity equal to or greater than racemic-TMQ. Each TMQ analogue also blocked the contractile responses of U46619 in rat aorta in a competitive manner, and the rank order of inhibition of U46619-induced contraction in rat aorta was I greater than VI greater than II = III greater than IV greater than V. N-Benzyl TMQ (VI) possessed the greatest potency for U46619 blockade and beta 2/beta 1-selectivity ratio of the N-substituted analogues. The results show that varying the N-substituents on TMQ produces compounds which retain beta 2-selectivity and give a different activity profile for beta-adrenoceptor activation vs. endoperoxide/thromboxane A2 antagonism.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

5-fluoro- and 8-fluorotrimetoquinol: selective beta 2-adrenoceptor agonists.

The 5-fluoro and 8-fluoro analogues of trimetoquinol, TMQ, have been synthesized and evaluated for beta 2- and beta 1-adrenoceptor activity in guinea pig trachea and atria, respectively. The fluoro analogues of TMQ maintained potent beta 2-adrenoceptor agonist activity but had reduced beta 1-adrenoceptor agonist activity. The changes in beta 1-activity of these compounds were correlated to differences in phenolic pKa's. The beta 1- and beta 2-adrenoceptor actions of 2 and 3 were blocked in a competitive manner by propranolol. The enhanced beta 2/beta 1 selectivity for the analogues was found to be 8-fluoro analogue 3 greater than 5-fluoro analogue 2 greater than trimetoquinol (1).

Adrenergic beta-Agonists↗
PubMed1987

Dissociation of hypolipidemic and antiplatelet actions from adverse myotonic effects of clofibric acid related enantiomers.

Enantiostructure-activity studies of chlorophenoxybutyric and propionic acids have provided evidence for the dissociation of serum cholesterol lowering and platelet antiaggregatory activities from the adverse chloride ion channel mediated myotonic effects of these compounds. R-(+) propionic and butyric acid enantiomers, unlike achiral clofibric acid and the S-(-) isomers, did not inhibit chloride conductance in rat extensor digitorum longus muscle fibers in vitro but, like clofibric acid and the S-(-) isomers, retained the serum cholesterol lowering activity in a cholesterol-fed rat model. Additionally, a stereoselective and greater inhibition was observed for the R-(+) isomers against adenosine diphosphate and arachidonic acid induced human platelet aggregation.

2-Methyl-4-chlorophenoxyacetic Acid↗
PubMed1987

Synthesis and platelet antiaggregatory activity of trimetoquinol analogs as endoperoxide/thromboxane A2 antagonists.

Trimetoquinol (TMQ) has activity as a beta-adrenergic agonist and as a platelet antiaggregatory agent. Recent reports from this and other laboratories have focused on the mechanism of inhibition of platelet function by TMQ and its analogs. Based on its competitive and stereoselective inhibition of thromboxane mimetic agents, TMQ was proposed as an endoperoxide/thromboxane A2 receptor antagonist; however, this mechanism has been questioned. A radiolabeled TMQ analog with high specific activity would aid in the elucidation of the actual mechanism of action. In the current research, modifications of the trimethoxy ring system of TMQ have been investigated. Replacement of one or two of the methoxy groups with iodine atoms leads to retention of platelet antiaggregatory activity and agonist blocking activity. Thus, these analogs have promise as potential radioligands since iodide exchange labeling can provide 125I-labeled compounds. Further, replacement of a methoxy group with either a nitro or amino functionality leads to decreased activity in platelet systems. These results suggest that the putative sites of interaction for the trimethoxy ring system of TMQ in platelet systems will tolerate large, lipid soluble groups but will not tolerate large changes in the electronic characteristics of the ring system.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Alpha-adrenoceptor-mediated actions of optical isomers and desoxy analogs of catecholimidazoline and norepinephrine in human platelets: in vitro.

Adrenoceptor-mediated effects of the enantiomers of optically active imidazoline, 2-(3,4,alpha-trihydroxybenzyl imidazoline (catecholimidazoline; CI), and norepinephrine (NE), and the corresponding desoxy derivatives, 2-(3,4-dihydroxybenzyl)imidazoline (desoxy-CI) and dopamine, have been investigated in human platelets. Differences between responsiveness of platelets from donor to donor were observed in the presence of the isomers and the desoxy analogs of NE and CI. In certain platelet preparations, all compounds gave concentration-dependent stimulatory responses, whereas in other preparations, only R(-)-NE and R(-)-CI were inducers of platelet aggregation and serotonin release. The rank order of stimulatory potencies (EC50; microM) for CI and NE was R(-)-NE (1.3) greater than R(-)-CI (7.5) greater than S(+)-NE (19) = S(+)-CI (20) = dopamine (22) greater than desoxy-CI (greater than 35). Unlike R(-)-CI, both S(+)-CI and desoxy-CI were either agonists or antagonists of human platelet function. In preparations unresponsive to the S(+)-isomers or desoxy analogs, the potencies (EC50) for R(-)-NE and R(-)-CI were 1.7 and 7.7 microM respectively. The corresponding inactive CIs [S(+)-CI and desoxy-CI] were inhibitors of both primary and secondary phases of aggregation and serotonin release responses to R(-)-CI and R(-)-NE, respectively. In contrast, the aggregation responses to ADP, arachidonic acid or U46619 were not blocked by S(+)-CI or desoxy CI. The rank order of inhibitory potencies for selected alpha-adrenoceptor agents against R(-)-NE was phentolamine greater than clonidine greater than desoxy-CI greater than S(+)-CI. Moreover, the relative inhibitory potencies of phentolamine and desoxy-CI against aggregation responses to R(-)-NE and R(-)-CI, respectively, were the same. These results suggest that the enantiomers and desoxy derivatives of CI and NE mediate their effects in human platelets by an interaction with alpha-adrenoceptors; catecholamines and imidazolines interact with the same alpha-adrenoceptors in human platelets; the stereochemical requirements of both chemical classes for stimulatory activity in human platelets adhere to the Easson-Stedman hypothesis in this alpha 2-adrenoceptor system; and desoxy-CI possessed the highest potency as an antagonist of alpha-adrenoceptors which suggests that the hydroxy group at the benzylic carbon atom of these imidazolines may not be required for maximal binding to adrenoceptors in platelets.

Blood Platelets↗
PubMed1986

Synthesis and investigation of the beta-adrenoceptor agonist and platelet antiaggregatory properties of 1,7,8-trisubstituted 2,3,4,5-tetrahydro-1H-2-benzazepine analogues of trimetoquinol.

The synthesis and biological evaluation of 7,8-dihydroxy (2) and 7,8-methylenedioxy (3) analogues of 1-[(3,4,5-trimethyoxyphenyl)methyl]-2,3,4,5-tetradhyo-1H-2-b enzazepine on beta-adrenoceptor systems and human platelets were undertaken and compared with trimetoquinol (TMQ, 1). Whereas 1 is a potent beta-adrenoceptor agonist in guinea pig atria and trachea (pD2 = 8.2), analogue 2 was marginally effective at relaxing guinea pig tracheal smooth muscle (pD2 = 4.4) and inactive as an agonist on guinea pig atria. Analogues 2 and 3 were inhibitors of phospholipase C (PLC; from Clostridium perfringens) induced and secondary wave of ADP-induced aggregation responses and inactive against low-dose thrombin-induced or stable endoperoxide (U46619) induced human platelet aggregation. Against ADP-induced serotonin secretion, 3 was 9-fold more active than analogue 2. Further, the rank order of TMQ isomers and 3 as inhibitors of PLC-induced platelet aggregation, serotonin secretion, and phosphatidylinositol degradation was identical (3 greater than (S)-(-)-1 greater than (R)-(+)-1). The results suggest that these compounds are blocking the action of PLC by interfering with phosphatidylinositol turnover in platelet membranes. The inhibition of ADP-induced responses in human platelets by analogues 2 and 3 also suggests a site of inhibition at a level of arachidonic acid release. Thus, ring expansion of 1 as in the benzazepine analogues 2 and 3 has allowed us to develop selective inhibitors of platelet function that lack significant beta-adrenoceptor activity.

Adenosine Diphosphate↗
PubMed1986

Syntheses and beta-adrenergic agonist and antiaggregatory properties of N-substituted trimetoquinol analogues.

Trimetoquinol [1-(3,4,5-trimethoxybenzyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline, TMQ] is a potent beta-adrenergic receptor agonist and inhibitor of human platelet aggregation. Selective cleavage of O-benzyl groups in the presence of an N-benzyl group using HCl and formation of a cyclic sulfite ester from the reaction of a catechol with thionyl chloride were achieved. The N-substituents included methyl, benzyl, and beta-hydroxy- and beta-chloroethyl groups. Each N-substituted TMQ caused a concentration-dependent stimulation of beta 2 (trachea) and beta 1 (atria) adrenoceptor tissues and inhibition of 15(S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13(E)-dienoic acid (U46619, a thromboxane A2 mimetic) mediated human platelet activation. TMQ remained the most potent in the series. Structure-activity results indicated that the larger the N-substituent, the lower the beta-adrenergic activity but the higher the inhibition of platelet aggregatory activity. Thus, the structural requirements of these TMQ analogues for the two types of biological activity are different.

Adrenergic beta-Agonists↗
PubMed1986

Comparative antiaggregatory activity in human platelets of a benzopyranone aci-reductone, clofibric acid, and a 2,3-dihydrobenzofuran analogue.

A synthetic method for the preparation of aci-reductone 6-chloro-3,4-dihydroxy-2H-1-benzopyran-2-one (3) from 5-chlorosalicylate is presented. In human platelets, the benzopyranone derivative 3, clofibric acid (1), and the 2,3-dihydrobenzofuran analogue 4 inhibited aggregation and serotonin secretory responses to adenosine diphosphate (ADP) with a rank order of potency 3 greater than or equal to 4 greater than 1. Only analogues 3 and 4 consistently blocked the aggregatory responses (greater than 50%) to arachidonic acid (AA) and U46619, a thromboxane A2 agonist. Further, the rank order of inhibitory potency against U46619-induced serotonin secretion was 4 greater than 3 greater than 1. Benzopyranone 3 is of interest since it was the most potent inhibitor of thrombin-induced [3H]AA release (3 much greater than 4 = 1) and more potent than 1 or 4 for the blockade of the ADP- or AA-mediated pathway of platelet aggregation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

Inhibition of protein synthesis: a basis for tunicamycin-induced decrease in rat liver cytochrome P-450.

Tunicamycin caused a dose and time dependent decrease in cytochrome P-450 in rat liver. A dose of 50 micrograms/kg caused a decrease of about 50% in 72 hours. A similar decrease in the activities of rat liver microsomal aniline hydroxylase, aminopyrine N-demethylase and ethoxycoumarin O-deethylase were also seen after the tunicamycin treatment. Tunicamycin also suppressed food and water intake but the decrease in cytochrome P-450 was not related to these effects. NADPH cytochrome c reductase was not markedly decreased by tunicamycin. A decrease in cytochrome P-450 was also observed in cultured rat hepatocytes treated with tunicamycin. It decreased incorporation of [35S]-methionine into total proteins as well as into various cytochrome P-450 isozymes of rat hepatocytes. This indicates that a decrease in protein synthesis may be responsible for the tunicamycin-induced decrease in cytochrome P-450 and drug metabolism.

Animals↗
PubMed1985

Antagonism of prostaglandin-mediated responses in platelets and vascular smooth muscle by 13-azaprostanoic acid analogs. Evidence for selective blockade of thromboxane A2 responses.

Studies were undertaken to examine the pharmacological properties and stereochemical requirements of a limited series of prostanoic acid analogs for inhibition of arachidonic acid (AA) and/or endoperoxide (U46619)-mediated responses in human platelets and rat aorta. To assess the role of stereochemistry, a set of trans- and cis-isomers of 13-azaprostanoic acid (APA) and 11a-homo-13-azaprostanoic acid (HAPA) were prepared. Each prostanoic acid analog blocked AA- or U46619-induced aggregatory and secretory responses in platelets, and U46619-mediated contractions of rat aorta in a concentration-dependent manner (0.1 to 100 microM). The azaprostanoic acid analogs blocked responses to both inducers of platelet activation with IC50 values ranging from 3.4 to 27.5 microM. Trans-APA was about 2- to 3-fold more active as an antagonist of serotonin release induced by AA or U46619 than the remaining analogs. The rank order of inhibitory potency (IC50; microM) for these analogs against U46619-induced serotonin release in human platelets was trans-APA (3.4) greater than cis-APA (8.9) = cis-HAPA (8.7) = trans-HAPA (9.1). Concentrations of the prostanoic acid analogs required to block these responses to AA and U46619 were similar, and the highest concentration used (100 microM) did not modify AA-induced malondialdehyde production in human platelet preparations. In contrast, the isomers of APA and HAPA were equally active as antagonists of U46619-induced contractions of rat vascular tissue, possessing KB values varying from 7.1 to 13.2 microM. Each azaprostanoic acid analog shifted the concentration-response curve of U46619 in rat aorta to the right, indicating a competitive-type inhibition. In addition, the azoprostanoic acid analog (U51605) was a more potent competitive antagonist of U46619 in this preparation and possessed an average pKB value of 6.18. In summary, the results show that (1) expansion of the five-membered ring of APA to the six-membered ring analogs (HAPA) led to a retention of potent inhibitory activity against U46619 in human platelets and rat vascular smooth muscle, (2) the antiaggregatory and antisecretory actions of the azaprostanoic acid analogs were mediated by a blockade of the responses to AA and U46619, and not by an inhibition of AA metabolism, (3) the blocking activity for the APA isomers was stereoselective (trans greater than cis) whereas the isomers of HAPA were equally effective as inhibitors of platelet function; and (4) these azaprostanoic acid analogs act as selective endoperoxide (U46619)/thromboxane A2 antagonists in these two tissues.

Adult↗
PubMed1985

Effect of trimetoquinol analogs for antagonism of endoperoxide/thromboxane A2-mediated responses in human platelets and rat aorta.

The pharmacological properties of a limited series of tetrahydro-isoquinoline [trimetoquinol (TMQ)] analogs for inhibition of endoperoxide (U46619)-mediated responses in human platelets and rat aorta were examined. All analogs blocked U46619-induced aggregatory and secretory responses in platelets, and contraction of rat aorta in a concentration-dependent manner. R-(+)-TMQ was a competitive-type inhibitor of U46619-induced contractions of rat aorta. The relative inhibitory potency for TMQ analogs against U46619-induced effects was TMQ greater than N-methyl TMQ greater than or equal to erythro-alpha-methyl TMQ greater than threo-alpha-methyl TMQ greater than or equal to alpha-dimethyl TMQ. R-(+)-TMQ and the azoprostanoid analog (U51605) were potent antagonists of U46619 action in rat aorta with pA2 values of 5.97 and 5.70, respectively. Other experiments indicated that U51605 was a partial agonist and R-(+)-TMQ was an inhibitor of U51605-induced contractions of rat aorta (pKB = 5.94). R-(+)-TMQ also blocked prostaglandin E2-mediated responses in rat aorta (pA2 = 5.46) but was ineffective as an antagonist of prostaglandin F2 alpha and LTD4 responses in dog iris sphincter and guinea-pig trachea or lung parenchyma, respectively. The data indicate that 1) the TMQ analogs were antagonists of endoperoxide/thromboxane A2-mediated responses in rat aorta and human platelets involving a similar mechanism of action and 2) stereochemical requirements of these TMQ analogs for activation of beta adrenoceptors and antagonism of endoperoxide/thromboxane A2-mediated responses are different. It is concluded that selectivity for these two pharmacological properties of TMQ can be achieved by appropriate stereochemical modification of the tetrahydroisoquinoline nucleus.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1984

Human platelet activation by bacterial phospholipase C is mediated by phosphatidylinositol hydrolysis but not generation of phosphatidic acid: inhibition by a selective inhibitor of phospholipase C.

We have shown earlier that phospholipase C (PLC) from Clostridium perfringens causes human platelet aggregation and secretion in a concentration dependent manner. The present study was undertaken to further characterize the specificity of the effects of PLC and to better understand the mechanism of the action of this inducer. A methylene-dioxybenzazepine (MDBA) analog of trimetoquinol was synthesized and tested for antiplatelet activity. MDBA (3-30 microM) inhibited PLC-induced aggregation in a concentration dependent manner. Whereas up to 200 microM MDBA did not inhibit aggregation induced by either thrombin, arachidonic acid, or U46619. Effects of PLC (0.05 U/ml) on hydrolysis of phosphatidylinositol, production of phosphatidic acid and thromboxane B2 (TXB2) synthesis were investigated using [32P]-phosphate and [14C]-arachidonic acid labeled platelets. PLC (0.05 U/ml) caused a time dependent decrease in platelet phosphatidylinositol. Up to 50% of labeled phosphatidylinositol was lost from platelets in five minutes. MDBA (3-30 microM) inhibited PLC-induced loss of phosphatidylinositol in a concentration dependent manner. An increase in phosphatidic acid was also observed in PLC-stimulated platelets. Up to 100 microM MDBA did not inhibit production of phosphatidic acid. PLC-treated platelets did not produce any TXB2. In other experiments possible protease contamination of PLC preparations was tested by incubating PLC (0.03-0.5 U/ml) with [14C]-casein. PLC in concentrations up to ten times higher than the concentrations used in aggregation studies did not cause hydrolysis of [14C]-casein, whereas more than 30% of [14C]-casein was hydrolyzed by trypsin. PLC-induced aggregation was not inhibited by up to 300 microM adenosine or ATP. In other experiments, platelet aggregation by ADP was inhibited by adenosine and ATP in a concentration dependent manner. The addition of calcium (0.5- 2.0 mM) increased aggregation by PLC in a concentration dependent manner. These findings suggest that PLC-induced activation of platelets is: (a) dependent on phosphatidylinositol hydrolysis but not on the production of phosphatidic acid, TXB2 or secretion of ADP; (b) not caused by protease contaminants; (c) calcium dependent; and (d) MDBA inhibits PLC-induced aggregation by blocking phosphatidylinositol hydrolysis.

Adenosine↗
PubMed1983

Hypolipidemic effects of clofibrate and selected chroman analogs in fasted rats: II. High sucrose-fed animals.

The hypolipidemic properties of ethyl 6-chlorochroman-2-carboxylate (II), 6-phenylchroman-2-carboxylate (III) and 6-cyclohexylchroman-2-carboxylate (IV) were compared to clofibrate (I) in sucrose-fed fasted male Sprague-Dawley rats. All compounds were administered at doses of 0.2 and 0.4 mmol/kg, orally, twice daily for 7 consecutive days. In this model, II was a more effective hypocholesterolemic drug than clofibrate, whereas III and IV were inactive. Chlorochroman II, like clofibrate, decreased serum alpha-lipoprotein cholesterol and pre-beta-lipoprotein triglyceride concentrations and concomitantly increased serum beta-lipoprotein triglyceride concentrations. In clofibrate-treated rats, serum free cholesterol concentrations increased concurrent with a reduction in serum lecithin: cholesterol acyltransferase activity, but no such correlation was observed for II. Only II lowered liver cholesterol levels and increased liver triglyceride levels. No consistent inhibition of liver microsomal 3-hydroxy-3-methylglutaryl-CoA reductase activity was observed with these analogs. The observed changes in triglyceride and cholesterol concentrations among serum lipoproteins were of a greater magnitude after chlorochroman II and clofibrate administration to sucrose-fed rats than in our previous studies using chow-fed fasted rats. These data suggest that chloro-substitution at the 6-position of the phenylchroman ring is important for hypolipidemic activity of these cyclic clofibrate analogs.

Animals↗
PubMed1982

Evidence for the nonenzymatic and irreversible binding of cytembena to rat liver microsomes in vitro.

Characteristics of the irreversible binding of cytembena (CYT) to rat liver microsomal proteins have been investigated in vitro. Binding of [14C]CYT to rat liver microsomal proteins remained unchanged in the presence of SKF-525A or after heat denaturation and was not dependent upon the presence of pyridine nucleotide (NADPH or NADH). Ethacrynic acid, cysteine, dithiothreitol, and lysine were found to block the irreversible binding of [14C]CYT to microsomal proteins in a dose-dependent manner. The rank order of effectiveness as inhibitors of CYT binding was ethacrynic acid greater than cysteine greater than dithiothreitol greater than lysine. In other studies, CYT was shown to preferentially form adducts with cysteine rather than lysine or glycine. Using structural analogs and metabolites of CYT, it was found that 4-methoxybenzoylacrylic acid and beta-benzoylacrylic acid were effective competitors of [14C]CYT binding to liver microsomal proteins. By contrast, 4-methoxybenzoylpropionic acid, 5-(4-methoxyphenyl)dihydro-2(3H)furanone and 4-hydroxy-4-(4-methoxyphenyl)butyric acid were ineffective as inhibitors of the irreversible binding of CYT. These data suggest that sulfhydryl groups are involved in the nonenzymatic binding of CYT and that the presence of a carbon-carbon double bond in CYT, in debrominated metabolites or structural analogs, is requisite for an interference of the binding of CYT to microsomal proteins.

Acrylates↗