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At least 19 recordsLinked to original sources
PubMedDate not supplied

[Spasm-activity caused by interaction of benzo- and naphtho-1.3-dioxole-carboxylic acids of mice (author's transl)].

We describe the preparation of 4,7-dimethyl-benzo[1,3]dioxole-5-carboxylic acid (7 d), 5,6-dimethyl-benzo [1,3]dioxole-4-carboxylic acid (14), 6,7-dimethoxy-benzo [1,4]dioxane-5-carboxylic acid (16), 7,8-dimethyl-3,4-dihydro-2 H-benzo [1,5]dioxepin-6-carboxylic acid (17), and of 8,9-dimethyl-2,3,4,5-tetrahydro-benzo [1,6]dioxocin-carboxylic acid (18) by reaction of the lithiumcompounds with carbondioxide. For testing the spasm-activity of benzo [1,3]dioxole-5-carboxylic acids (Table I), benzo [1,3]dioxole-4-carboxylic acids (Table II), and naphtho [1,3]dioxole-carboxylic acids (Table III) these componds were orally given to mice.

Animals↗
PubMed1984

3-Hydroxy-alpha-methyltyrosine progenitors: synthesis and evaluation of some (2-oxo-1,3-dioxol-4-yl)methyl esters.

The (5-methyl-2-oxo-1,3- dioxol -4-yl)methyl and (5-tert-butyl-2-oxo-1, 3- dioxol -4-yl)methyl esters of 3-hydroxy-alpha-methyltyrosine (methyldopa) were prepared and evaluated as progenitors of the amino acid. 1H NMR experiments reveal that the esters are converted cleanly to methyldopa and the corresponding alpha-diketone at pH 7.4, with the 5-methyl derivative undergoing hydrolysis faster than the 5-tert-butyl analogue. Bioavailability studies in dogs show that the esters, particularly the 5-methyl derivative, yield significant plasma levels of methyldopa. Both esters are orally effective antihypertensive agents in spontaneously hypertensive (SH) rats. These studies indicate that (2-oxo-1,3- dioxol -4-yl)methyl esters are viable prodrugs for the latentiation of methyldopa.

Animals↗
PubMed2001

Inhalation toxicity of Dioxole and Dioxolane compounds in the rat.

Four chemicals (Dioxole 418, Dioxolane 418, Dioxolane 416 and Dioxolane 456) which are used as stabilizers in highresolution image were tested or both their acute and repeated inhalation toxicity in the rat using nose-only exposures. Acute studies determined the lethal concentrations following a single 4-hour exposure; repeated exposure inhalation studies determined the potency and target tissue(s) following 6-hour/day exposures, 5 days/week for 2 weeks. Each of the chemicals was at least mildly toxic acutely with approximate lethal concentrations of > 1,500 ppm for Dioxole 418, 1,300 ppm for Dioxolane 418, 1,700 ppm for Dioxolane 416, and 4,300 ppm for Dioxolane 456. No specific unusual clinical signs of response were seen in the rats exposed acutely. Repeated exposures with Dioxole 418 and Dioxolane 418 resulted in no evidence of toxicity with NOAEL's being 440 and 500 ppm respectively (the highest concentrations tested). Repeated exposures to 250 ppm Dioxolane 456 were not tolerated with mortalities observed after exposure. Severe bone marrow hypoplasia along with reductions in platelet and neutrophil counts were observed at this concentration with less severe hemopoietic changes seen also at 10 and 51 ppm. The no-effect level for Dioxolane 456 was determined to be 10 ppm in female rats and I ppm in males. The same hemopoietic effects were seen with Dioxolane 416 at exposures of 53 ppm or greater in males but not in females exposed to 53 ppm Dioxolane 416. Hepatocellular hypertrophy and depression of serum alkaline phosphatase activity were seen in male rats exposed to 500 but not 53 ppm Dioxolane 416. Testicular degeneration was also seen in rats exposed to 500 ppm Dioxolane 416. The NOAEL was 5 ppm for the chemical.

Administration, Inhalation↗
PubMed2006

Formal gas-phase polar [4 + 1+] cycloaddition of ionized methylene to alpha-dicarbonyl compounds: synthesis of 2-unsubstituted 1,3-dioxoles.

Ion/molecule reactions of +CH2OCH2. with alpha-dicarbonyl compounds were performed via pentaquadrupole mass spectrometry. Besides the previously known [3+ + 2] 1,3-cycloaddition reaction that forms cyclic 1,3-dioxonium ions, an unprecedented reaction proceeding formally by [4 + 1+] cycloaddition of ionized methylene (CH2+.) to the alpha-dicarbonyl compounds occurs competitively, leading to the gas-phase synthesis of several ionized 2-unsubstituted 1,3-dioxoles. This novel cycloaddition reaction may therefore be added to the set of methods available for the synthesis of 1,3-dioxoles.

Journal Article↗
PubMed2002

Structure-activity relationships of a novel class of endothelin-A receptor antagonists and discovery of potent and selective receptor antagonist, 2-(benzo[1,3]dioxol-5-yl)-6-isopropyloxy-4-(4-methoxyphenyl)-2H-chromene-3-carboxylic acid (S-1255). 1. Study on structure-activity relationships and basic structure crucial for ET(A) antagonism.

A novel series of endothelin-A (ET(A)) selective receptor antagonists having a 2H-chromene skeleton are described. A lead compound, 2-(benzo[1,3]dioxol-5-yl)-2H-chromene-3-carboxylic acid (3), was found by modifications of our own angiotensin II antagonist. A structure-activity relationship (SAR) study of 3 reveals that the structural requirements essential for potent and selective ET(A) receptor binding affinity are the m,p-methylenedioxyphenyl, carboxyl, and isopropoxy groups at the 2-, 3-, and 6-positions, respectively, on the (R)-2H-chromene skeleton. The substituent at the 4-position is also important for improving the activity, and various hydrophobic functional groups of 6-9 A such as liner, branched, and cyclic aliphatic groups, unsubstituted and substituted aryl groups, and even halogen atoms were acceptable. These results suggest that (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acid, formula 108, is the crucial basic structure to be recognized by the ET(A) receptor. The most potent compound is (R)-48 (S-1255), which binds to the ET(A) receptor with an IC(50) value of 0.19 nM and is 630-fold selective for the ET(A) receptor than for the ET(B) receptor. This compound has 55% oral bioavailability in rats. On the basis of the SAR, the roles of each substituent in the receptor binding are discussed.

Animals↗
PubMed1991

2-Oxo-1,3-dioxoles as specific substrates for measurement of arylesterase activity.

Various 4-arylthiomethyl-2-oxo-1,3-dioxole derivatives IIIa-o were synthesized. Their hydrolysis rates by arylesterase (EC 3.1.1.2) and cholinesterase (EC 3.1.1.8) in human serum were evaluated. Some of them were not hydrolyzed by cholinesterase, but were hydrolyzed easily by arylesterase. Among the substrates, sodium 4-((5-methyl-2-oxo-1,3-dioxol-4-yl)methylthio)benzenesulfonate (IIIg) was selected for its substrate reactivity toward arylesterase and its good water solubility. In addition, neither aliesterase (EC 3.1.1.1), acetylesterase (EC 3.1.1.6) nor cholesterol esterase (EC 3.1.1.13) hydrolyzed the compound. IIIg is thus concluded to be a specific substrate for arylesterase. Our assay system for serum arylesterase using IIIg can be readily applied to an automatic analyzer in the diagnosis of liver cirrhosis.

Carboxylic Ester Hydrolases↗
PubMed2002

Defective intracellular calcium handling in monocrotaline-induced right ventricular hypertrophy: protective effect of long-term endothelin-A receptor blockade with 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)- 4-oxobut-2-enoate-sodium (PD 155080).

We studied the effect of long-term treatment with the oral endothelin (ET) ET(A) antagonist 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)-4-oxobut-2-enoate-sodium (PD 155080; PD) on right ventricular intracellular calcium (Ca(2+)(i)) handling and cardiac and pulmonary artery function in control rats and rats with monocrotaline (MCT)-induced right-heart hypertrophy. Rats were given an intraperitoneal injection of either saline (controls; n = 9) or MCT (50 mg/kg; n = 12), resulting in pulmonary hypertension-induced myocardial hypertrophy, or MCT followed by the daily administration of PD (50 mg/kg) for 9 weeks (n = 9). After 9 weeks, right ventricular pressure was measured, and the hearts were removed and perfused in vitro. Right ventricular function and Ca(2+)(i) transients were recorded simultaneously on a beat-to-beat basis using aequorin. Surviving animals in the MCT group (58%) developed significant hypertrophy and had 2-fold higher right ventricular pressure and a prolonged duration of isovolumic contraction that correlated with a similar prolongation of the Ca(2+)(i) transient, indicating a reduced rate of Ca(2+) sequestration in hypertrophy (P < 0.05 versus control). In the PD group, all animals survived, and right ventricular pressure, diastolic relaxation, Ca(2+) transport kinetics, and peak systolic and end-diastolic wall stress were all normalized (P > 0.05 versus control); and pulmonary artery endothelial function was partly restored (P < 0.05 versus MCT and control groups). These results demonstrate for the first time that long-term ET(A) receptor antagonism normalizes myocardial cytosolic Ca(2+) modulation, which may contribute to the antihypertrophic and cardioprotective effect of ET(A) receptor therapy in this model.

Aequorin↗
PubMed2004

Synthesis and KCNQ2 opener activity of N-(1-benzo[1,3]dioxol-5-yl-ethyl, N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl, and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl acrylamides.

Bioisosteric replacement studies led to the identification of N-(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide ((S)-3) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)-N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide ((S)-4), and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-5) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 microM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (+/-)-3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds (S)-4 and (S)-5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.

Acrylamides↗
PubMed2002

A novel class of endothelin-A receptor antagonists, (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropyloxy-2H-chromene-3-carboxylic acids (S-1255). Conformational analysis of basic structure, crucial for ET(A) antagonism, in solution and solid states.

Conformational studies of potent and selective endothelin-A (ET(A)) receptor antagonists, 4-substituted (R)-2-(benzo[1,3]-dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acids, are reported. X-ray crystallography and NMR studies of the 4-anisyl derivative 2 (S-1255), the stable atropisomers 3 and the 4-n-butyl derivative 4 reveal that the A-, B- and C-rings in these compounds adopt a L-like conformation in both solution and solid states. Molecular mechanics calculation shows that this L-like conformation is an inevitable conformation as determined by intramolecular steric repulsions. These 2H-chromene derivatives bound to an ET(A) receptor with IC(50) values of less than 1 nM, whereas the dihydro compounds 7 and 9 not having the L-like conformation showed weaker affinities. These results suggest that the L-like conformation is specifically recognized by the active site of the ET(A) receptor. The roles of the L-like conformation in the receptor binding are discussed.

Acids, Heterocyclic↗
PubMed2001

Endothelin receptor antagonist activity of (R)-(-)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropylphenylsulfonyl)-2-(6-methyl- 2-propylpyridin-3-yloxy)acetamide hydrochloride (PABSA) in rat aortic smooth muscle cells and isolated rat thoracic aorta.

Antagonist activities of (R)-(-)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropylphenylsulfonyl)-2-(6-methyl- 2-propylpyridin-3-yloxy) acetamide hydrochloride (CAS 188710-94-3, PABSA), a novel endothelin (ET) receptor antagonist, for ETA and ETB receptors were evaluated using rat aortic smooth muscle A7r5 cells and isolated rat thoracic aorta. PABSA concentration-dependently inhibited the ET-1-induced increase in intracellular calcium concentration ([Ca2+]i) mediated via ETA receptors in A7r5 cells with an IC50 of 0.17 nmol/l. PABSA antagonized the ETA receptor-mediated contraction induced by ET-1 in endothelium-denuded rat aorta with a Kb of 0.74 nmol/l. The potency of PABSA in inhibiting ETA receptor-mediated vasocontraction was approximately 40- and 100-fold greater than those of BQ-123, a selective ETA antagonist, and bosentan, a mixed ETA/ETB receptor antagonist, respectively. ETB receptor-mediated endothelium-dependent vasorelaxation induced by ET-3 in the aorta was also antagonized by PABSA, with a Kb of 9.8 nmol/l. In contrast, PABSA affected neither the vasocontraction induced by KCl or norepinephrine nor the vasorelaxation induced by acetylcholine or prostaglandin I2 in the aorta. These results suggest that PABSA is a highly potent and selective ETA receptor antagonist.

Animals↗
PubMed2006

[Preparation and characterization of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl thiamine sulfides].

A new type of S-protected thiol-type thiamines (prodrugs), which have a (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group recognized as a biologically safe promoiety, were designed, prepared, and confirmed to show higher serum thiamine levels after oral administration to rats than after that of thiamine itself and bisbentiamin as standards. Thus it was shown that the promoiety should be also used for improvement of poor oral absorption of drugs with a mercapto group, in addition to the absorption of drugs with carboxyl, amino, and hydroxyl groups.

Administration, Oral↗
PubMed1989

Studies of dioxole ring substituted 3,4-methylenedioxyamphetamine (MDA) analogues.

The 3,4-ethylidenedioxy and 3,4-isopropylidenedioxy analogues, EDA and IDA, respectively, of 3, 4-methylenedioxyamphetamine (MDA) were compared to MDA in drug-stimulated [3H]-serotonin overflow from prelabelled rat hippocampal slices, [3H]-dopamine overflow from prelabelled rat caudate slices, in their ability to displace the 5-HT2 agonist R-[125I]-DOI from rat brain cortical binding sites. They were also compared in the two-lever drug discrimination assay in rats, utilizing d-LSD tartrate (0.08 mg/kg) or MDMA.HCl (1.75 mg/kg) as the training stimulus. MDA and EDA were nearly equipotent in inducing release of both [3H]-monoamine transmitters, while IDA was considerably less potent. Pretreatment of hippocampal slices with the 5-HT-uptake inhibitor fluoxetine (3.2 microM) blocked the [3H]-5-HT overflow induced by MDA. In the drug discrimination experiments, complete substitution occurred with all three drugs in both LSD- and MDMA-trained rats. The ED50 values indicated that MDA had about twice the potency of EDA, and five times the potency of IDA in MDMA-trained rats. In the LSD-trained animals, MDA was about three times more potent than EDA and about seven times more potent than IDA. The KI values for displacement of R-[125I]-DOI generally parallel the results of the LSD transfer tests.

3,4-Methylenedioxyamphetamine↗
PubMed1979

Steric effects of substituents on phenethylamine hallucinogens. 3,4-(Methylenedioxy)amphetamine analogues alkylated on the dioxole ring.

The compounds 1-(2-methyl-1,3-benzodioxol-5-yl)-2-aminopropane and 1-(2,2-dimethyl-1,3-benzodioxol-5-yl)-2-aminopropane were synthesized and evaluated for pharmacologic effects in mice. These can be viewed as analogues of the known psychotomimetic agent 3,4-(methylenedioxy)amphetamine (MDA). Their hydrochloride salts were compared with MDA for their ability to increase spontaneous motor activity and to elicit behavioral effects. The former compounds was MDA-like in action, while the latter was not. The results suggest that one face of the molecule must be free of steric bulk to possess activity.

3,4-Methylenedioxyamphetamine↗