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At least 55 records · Page 3Linked to original sources
PubMed1988

Induction of endothelial cell migration by proline analogs and its relevance to angiogenesis.

The proline analogs cis-4-hydroxy-L-proline, 3,4-dehydro-L-proline, and 2-azetidinecarboxylic acid induced increases in the migration rate of retinal capillary endothelial cells, aortal endothelial cells, corneal endothelial cells, aortal smooth muscle cells, and retinal pericytes. cis-4-hydroxy-D-proline did not. The optimal concentration for migration induction by any of the active agents was approximately 10(-5) M. At higher concentrations (5 x 10(-4) M) migration was not induced or was inhibited. When tested by subcutaneous implant assays in rabbits, cis-4-hydroxy-L-proline and 2-azetidinecarboxylic acid consistently elicited a marked angiogenic response. Whereas these compounds are known to modulate collagen synthesis and secretion, the concentrations at which they are effective inducers of migration suggest that they may have a more specific target than general collagen synthesis.

Animals↗
PubMed1979

Effects of anticalcifying and antifibrobrotic drugs on pre-established atherosclerosis in the rabbit.

The effects of the anticalcifying drug, ethane-hydroxydiphosphonate (EHDP) and the inhibitors of collagen biosynthesis, colchicine, penicillamine and azetidine were studied in the rabbit with pre-established atherosclerosis. The drugs were administered with a cholesterol-free diet (regression diet) for 8 weeks following the induction of atherosclerosis by feeding a hypercholesterolemic diet containing 2% cholesterol and 8% peanut oil for 8 weeks. The extent and severity of aortic atherosclerosis, as revealed by the morphological and biochemical findings, increased significantly during the regression period. In rabbits treated with EHDP (5 mg/kg/day) the aorta had fewer gross lesions and contained significantly less cholesterol, collagen and elastin than did the aorta of the rabbits fed the regression diet alone. These changes were associated with a significant reduction in aortic calcium caused by EHDP. The aortic content of cholesterol, collagen and elastin in the EHDP-treated rabbits, although less than that of the rabbits fed the regression diet alone, was about the same as that of the rabbits fed a high cholesterol diet for 8 weeks. Both colchicine (0.2 mg/kg/day) and penicillamine (100 mg/kg/day) had a selective action on the induced plaques in that they suppressed the fibrous proliferation in the lesions without preventing lipid and calcium accumulation in the lesions. Neither colchicine nor penicillamine reduced the extent of aortic atherosclerosis as determined by gross examination of the vessel. Azetidine had no significant effect on the pre-established atherosclerotic lesions. The lipid, fibrous protein and calcium content of the aorta of the azetidine-treated animals was not significantly different from that of the untreated animals. The biochemical findings in the aorta were consistent with the microscopic changes.

Animals↗
PubMed1985

An assessment of the importance of error-prone repair and point mutations to forward mutation to L-azetidine-2-carboxylic acid resistance in Escherichia coli.

By comparison of E. coli WP2 with CM891 (uvrA- pKM101) we found that pKM101 plasmid and uvrA- mutation considerably enhanced both spontaneous and chemically-induced reversion at the trp locus. However, little or no increase was observed for forward mutation at the A2C locus. Furthermore, mutation frequency decline was considerably greater for trp reversion than for mutation to A2Cr. Thus neither error-prone repair nor point mutation seemed likely to be the major mechanism for forward mutation at the A2C locus. Results for spontaneous mutation of recA-, polA- and gyrA- strains showed that polA- and gyrA- gave good increases in forward mutation but not in reversion. It was inferred that deletion, transposition and/or larger chromosomal effects rather than point mutation were mainly responsible for most forward mutation.

Azetidinecarboxylic Acid↗
PubMed1987

Mugineic acid: non-selective enhancement of excitatory amino acid actions on rat central neurones.

The effects of mugineic acid upon excitations induced by quisqualic acid (quis), N-methyl-D-aspartic acid (NMDA) and kainic acid (kain) on rat central neurones were examined in vivo through microiontophoretic drug administration in anaesthetized rats. Mugineic acid usually caused a non-selective enhancement of drug-induced excitations, occasionally producing direct excitation itself or increasing the rate of spontaneous discharge. Mugineic acid-induced effects were not blocked by the NMDA selective antagonist, 2-amino-5-phosphonovaleric acid (AP5).

Amino Acids↗
PubMed1989

Effects of a new analogue of thyrotropin-releasing hormone on pentobarbital-induced sleeping time in rodents.

The effects of a new analogue of TRH, YM-14673 (N-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate) on pentobarbital-sleeping time were observed in comparison with those of TRH in rodents. The YM-14673 was administered intravenously, orally and intramuscularly. In all cases it reduced pentobarbital-sleeping time in rats and/or mice in a dose-dependent manner. The analeptic activity of YM-14673 was about 10 times greater than that of TRH. Analeptic action was also observed with successive intravenous injections of YM-14673, once daily for 5 and 14 days in mice, suggesting that the drug induced no tolerance. In addition, there was evidence that the pituitary-thyroid axis was not necessary for the analeptic effects of YM-14673. In particular, it was noted that hypophysectomy did not reduce the antagonism by YM-14673 of pentobarbital-induced sleep and intracerebrally administered YM-14673 produced analeptic actions in mice. Pretreatment with atropine and baclofen antagonized the ability of YM-14673 to reduce sleep, induced by pentobarbital in mice. However, the analeptic action of YM-14673 was not reduced by the administration of haloperidol and phentolamine. These results suggest that YM-14673 produced facilitatory effects on the central nervous system, independent of an effect on the pituitary gland, and that the antagonizing effects by YM-14673 on the actions of pentobarbital may be affected by activation of the central cholinergic system as well as by inhibition of the GABA-ergic system.

Animals↗
PubMed1990

Effects of a new analog of thyrotropin-releasing hormone, N alpha-[(S)-4-oxo-2-azetidinyl) carbonyl]-L-histidyl-L-prolinamide dehydrate (YM-14673) on spinal reflex potentials and flexor reflexes in spinalized rats.

Experiments were performed on spinalized rats, transected at the Cl level. The intravenous administration of TRH and its analog YM-14673 (N alpha-[(S)-4-oxo-2-azetidinyl) carbonyl]-L-histidyl-L-prolinamide dehydrate) produced marked increases in the amplitude of mono- and polysynaptic reflex potentials and those of the withdrawal flexor reflexes. The effects of YM-14673 were stronger and longer-lasting than those of TRH. The stimulant action of TRH and YM-14673 on the flexor reflexes was not antagonized by prazosin, chlorpromazine, haloperidol or cyproheptadine, suggesting no involvement of the release of catecholamines or serotonin in the stimulant effects of TRH and its analog. Therefore, YM-14673 may be beneficial for the treatment of several spinal motor neuron diseases.

Animals↗
PubMed1990

Effects of a new TRH analogue, YM-14673, on disturbance of passive avoidance learning in senescence-accelerated mice.

Effects of a new TRH analogue, YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate), on disturbance of passive avoidance behavior were observed in senescence-accelerated mice (SAM). Latency of step-through in SAM-P/8/Ta (SAM-P/8, senescence-prone substrain) was significantly shorter than that in SAM-R/1/Ta (SAM-R/1, senescence-resistant substrain). Successive oral administration of YM-14673 (1 and 10 mg/kg) and TRH (10 mg/kg) for 3 weeks prolonged the shortened latency of step-through. These results suggest that YM-14673 is more potent than TRH in antiamnesic activities.

Aging↗
PubMed1976

Biochemical characterization of azetidine carboxylic acid-resistant Chinese hamster cells.

We have isolated variants of Chinese hamster lung (CHL) fibroblasts with decreased sensitivity to the toxic proline analog, L-azetidine-2-carboxylic acid (AZCA). Resistance to AZCA is a stable characteristic of these cell lines since it is maintained after 40 generations in nonselective medium. Two AZCA-resistant cell lines overproduce and excrete more proline than wild-type cells. Furthermore, AZCA rapidly inhibits the synthesis of proline from glutamic acid in wild-type but not the resistant cell lines. These studies suggest that resistance to AZCA in these cell lines is due to an alteration in some component of the proline biosynthetic pathway, possibly a regulatory site that is inhibited by AZCA.

Azetidines↗
PubMed1975

Effect of L-azetidine 2-carboxylic acid on growth and proline metabolism in Escherichia coli.

The effects of L-azetidine 2-carboxylic acid on growth and proline metabolism in a proline-requiring auxotroph of Escherichia coli are described. The homologue inhibited growth of the wild type and it, alone, did not substitute effectively for proline as a growth supplement for the mutant. In medium containing 0.05 mM proline, the addition of increasing amounts of homologue progressively inhibited growth of the wild type but stimulated growth of the mutant at homologue: proline ratios of 10 : 1 and 50 : 1. This suggested that the homologue exerted a "sparing effect" on proline in the mutant. The incorporation of L-[U-14C]proline and L-[3H]azetidine 2-carboxylic acid into hot trichloroacetic acid-insoluble material in the mutant was measured. Amino acid analysis of the insoluble material from cells incubated with radiolabeled proline alone revealed that proline was partially degraded and metabolized to other amino acids prior to incorporation into protein. The addition of unlabeled homologue to the incubation medium significantly reduced proline catabolism, suggesting that the homologue exerted a sparing effect on proline in this mutant. In medium containing unlabeled proline and radiolabeled L-azetidine 2-carboxylic acid, the homologue was incorporated both intact and partially degraded prior to incorporation into protein. Alanine was the major L-azetidine 2-carboxylic acid catabolite.

Amino Acids↗
PubMed1990

Pharmacodynamics and pharmacokinetics of AHR-11748, a new antiepileptic agent, in rodents.

AHR-11748, the desmethyl metabolite of fluzinamide (an effective antiepileptic), was active in preventing maximal seizures induced in mice or rats by electroshock and threshold seizures induced in mice by Metrazol, bicuculline, and picrotoxin. The compound showed a profile of anticonvulsant activity similar to those of phenobarbital and valproic acid and different from those of phenytoin and ethosuximide. ED50s were less than those of valproic acid, but greater than those of phenobarbital. Analysis of plasma and whole brain homogenates of mice indicated that AHR-11748 has an apparent terminal half-life (t1/2, beta) of 1.0 h. The brain:plasma ratio of AHR-11748 was 3.4:1 from 0.5 h to 6 h.

Administration, Oral↗
PubMed1986

Reversed-phase high-performance liquid chromatographic assay for the determination of potency and impurities in tazadolene succinate bulk drug and capsules.

A reversed-phase assay based on high-performance liquid chromatography with a water-acetonitrile-tetrahydrofuran (THF)-triethylamine (TEA)-perchloric acid (pH 2.5) mobile phase and a Zorbax C8 column has been validated for the determination of the purity of tazadolene succinate (I) [E-(+/-)-1-(2-benzylidenecyclohexyl)azetidine succinate, U-53996H] bulk drug, the potency of tazadolene succinate hard-filled capsule formulations and impurity levels in bulk drug. The system resolves E- and Z-isomers and other structurally related molecules. Retention of these compounds is mainly dependent on the amount of acetonitrile and THF in the mobile phase. An amine must be present in the mobile phase to bring about elution of I. The potency assay utilizes testosterone as internal standard. Potency assays exhibited relative standard deviations (R.S.D.) of less than 1%. Quantitative recovery from hard-filled capsules (HFC) is obtained by using a simple extraction procedure. Potential process impurities, potential degradation products, and formulation excipients are resolved. The assay is linear for tazadolene succinate concentrations equivalent to 50-150% of the assay concentration. Impurities can be quantitated to levels equivalent to about 0.1% by weight with R.S.D. less than 5%. The estimated limit of detection for I is about 2 ng for a 20 microliters injection.

Analgesics↗
PubMed1983

Azetidine-2-carboxylic acid contaminated dietary proline as a cause of urinary excretion of 4-amino-2-(S-cysteinyl)butyric acid in patients on oral treatment with a synthetic diet.

Three children with branched-chain ketoaciduria (maple syrup urine disease) were found to excrete an abnormal amino acid when they were on an artificial diet. This substance was identified as 4-amino-2-(S-cysteinyl)butyric acid with the use of column liquid chromatography, gas chromatography--mass spectrometry of various derivatives, and 360 MHz 1H-NMR spectroscopy. The same compound was detected in urine samples from subjects undergoing an oral loading test with L-proline. The chromatographic analysis of commercial proline from two sources indicated that one of the batches was contaminated (less than 1%) with L-azetidine-2-carboxylic acid (the homologue of proline with a four-membered ring). The latter compound is probably metabolized by the human via ring-opening and addition of a cysteine moiety. It is highly probable that the artificial diet given to the patients contained the impure proline and that the L-azetidine-2-carboxylic acid in the proline gave rise to the excretion of the 4-amino-2-(S-cysteinyl)butyric acid.

Azetidinecarboxylic Acid↗
PubMed1984

Simultaneous determination of fluzinamide and three of its active metabolites in plasma by high-performance liquid chromatography.

A sensitive and selective high-performance liquid chromatographic method has been developed for a new anticonvulsant, fluzinamide, and three of its active metabolites. This method requires only 0.5 ml of plasma, and it involves a single extraction with a mixture of hexane--dichloromethane--butanol (55:40:5). The plasma extract is chromatographed on a 10-micron, C18 reversed-phase column and quantitated by ultraviolet absorbance at 220 nm. The concentration--response curves for all four compounds are linear from 0.05 micrograms/ml to at least 10 micrograms/ml. The extraction efficiency of this method is greater than 90%. The accuracy and precision of the method were tested by analyzing spiked unknown samples that had been randomly distributed across the concentration range. The mean concentrations found were within +/- 9% of the various amounts added with a standard deviation of +/- 3.5%. This method has been successfully applied to the analysis of samples obtained from fluzinamide-dosed dogs, healthy unmedicated volunteers, and patients who were at steady state with phenytoin, carbamazepine, and fluzinamide.

Anticonvulsants↗
PubMed1975

Biosynthesis of the polyoxins, nucleoside peptide antibiotics: a new metabolic role for L-isoleucine as a precursor for 3-ethylidene-L-azetidine-2-carboxylic acid (polyoximic acid).

The biosynthetic origin of the carbon skeleton of 3-ethylidene-L-azetidine-2-carboxylic acid (polyoximic acid) is described. This unique cyclic amino acid is the C terminus of the nucleoside peptide antibiotics, the polyoxins, elaborated by Streptomyces cacaoi var, asoensis. In vivo experiments show that 14-C from [1-14-C]isoleucine, [U-14-C]isoleucine, [1-14-C]methionine, [U-14-C]methionine, [U-14-C]threonine, and [1-14-C]glutamate is incorporated into polyoximic acid; however, 14-C from [5-14-C]glutamate and [methyl-14-C]methionine is not incorporated. The distribution of 14-C in polyoximic acid clearly shows that the intact carbon skeleton of L-isoleucine is utilized directly. The incorporation of 14-C from [U-14-C]methionine, [U-14-C]threonine, and [1-14-CA1glutamate into polyoximic acid occurred only after their conversion to isoleucine via 2-ketobutyrate. A scheme is presented in which either of the two beta-unsaturated amino acids isolated from Bankera fuligineoalba, L-2-amino-3-hydroxymethyl-3-pentenoic acid or L-2-amino-3-formyl-3-penetenoic acid, is regarded as a possible intermediate amino acid between isoleucine and polyoximic acid.

Antifungal Agents↗