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PubMed1991

Intrastriatal injection of a selective metabotropic excitatory amino acid receptor agonist induces contralateral turning in the rat.

The consequence of in vivo activation of the phosphoinositide-coupled (metabotropic) excitatory amino acid (EAA) receptor subtype was investigated. We report that unilateral intrastriatal injection of 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), a selective metabotropic EAA receptor agonist, produced turning behavior (rotations) contralateral to the site of injection. This effect peaked at 5 to 8 hr after injection and was dose-related (EC50 = 0.59 mumol), producing a maximal effect at 1 mumol (32 +/- 4 rotations per 5 min). 1S,3R-ACPD-induced rotations were not mimicked by intrastriatal injection of vehicle (2 microliters of normal saline) or up to 2 mumol of 1R,3S-ACPD, the inactive ACPD isomer at the metabotropic EAA receptor. The selective competitive N-methyl-Daspartate receptor antagonist LY27461 4 (up to 5 mg/kg i.p) did not significantly affect 1S,3R-ACPD-induced rotations. However, coinjection of the metabotropic EAA receptor antagonist L-2-amino-3-phosphonopropionic acid (1 mumol) significantly reduced 1S,3R-ACPD-induced contralateral rotations. 1S,3R-ACPD at a dose which produced maximal contralateral rotations did not produce any loss of striatal gamma-aminobutyric acid neurons as indexed by glutamic acid decarboxylase enzyme activity in the injected striatum. In contrast to 1S,3R-ACPD, a dose of N-methyl-D-aspartate (0.2 mumol), which only very modestly induces contralateral rotations results in highly significant neuronal degeneration (50% loss of glutamic acid decarboxylase activity), and is associated with other excitatory behaviors such as clonic convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis.

The relation between the antithrombotic effect in vivo, and the inhibition constant (Ki) and the association rate constant (k(on)) in vitro was investigated for eight different thrombin inhibitors. The carotid arteries of anaesthetized rats were exposed to FeCl3 for 1 h, and the thrombus size was determined from the amount of incorporated 125I-fibrinogen. The thrombin inhibitors were given intravenously, and complete concentration- and/or dose-response curves were constructed. Despite a 50,000-fold difference between the Ki-values comparable plasma concentrations of hirudin and melagatran were needed (0.14 and 0.12 micromol l(-1), respectively) to obtain a 50% antithrombotic effect (IC50) in vivo. In contrast, there was a comparable in vitro (Ki-value) and in vivo (IC50) potency ratio for melagatran and inogatran, respectively. These results can be explained by the concentration of thrombin in the thrombus and improved inhibition by the low-molecular-weight compounds. For all eight thrombin inhibitors tested, there was an inverse relationship between k(on)-values in vitro and the slope of the dose response curves in vivo. Inhibitors with k(on)-values of < 1 x 10(7) M(-1) s(-1) gave steep dose response curves with a Hill coefficient > 1. The association time for inhibition of thrombin for slow-binding inhibitors will be too long to give effective antithrombotic effects at low plasma concentrations, but at increasing concentrations the association time will decrease, resulting in a steeper dose-response curve and thereby a more narrow therapeutic interval.

Amino Acid Chloromethyl Ketones↗
PubMed1984

Anticonvulsant and proconvulsant properties of a series of structural isomers of piperidine dicarboxylic acid.

Anticonvulsant and convulsant effects of various piperidine dicarboxylic acids have been evaluated following their intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection in DBA/2 mice, a strain of mice genetically susceptible to sound-induced seizures. Protection against sound-induced seizures occurred after intraventricular administration of (+/-)cis-2,3-piperidine dicarboxylic acid (0.017-0.045 mumol), (+/-)trans-2,3-piperidine dicarboxylic acid (0.018-0.33 mumol) and (+/-)cis-2,4-piperidine dicarboxylic acid (0.57-1.68 mumol). Protection against sound-induced seizures occurred after intraperitoneal injection of (+/-)cis-2,3-piperidine dicarboxylic acid (0.52-1.8 mmol/kg). Myoclonus or convulsions occurred at various times after the intraventricular injection of cis-2,3-piperidine dicarboxylic acid, trans-2,3-, cis-2,4-, cis-2,5- and cis-2,6-, piperidine dicarboxylic acids, and after the intraperitoneal injection of trans-2,3-piperidine dicarboxylic acid. The latter effect was blocked by pretreatment with 2-amino-7-phosphonoheptanoic acid (0.33 mmol/kg, i.p.) a potent and specific antagonist of excitation induced by N-methyl-D-aspartate. The anticonvulsant action of cis-2,3-piperidine dicarboxylic acid and the convulsant action of trans-2,3-piperidine dicarboxylic acid were associated with predominant antagonist and agonist actions respectively, at receptors preferring N-methyl-D-aspartate.

Acoustic Stimulation↗
PubMed2006

Proline/pipecolinic acid-promoted copper-catalyzed P-arylation.

We have developed a convenient and efficient approach for P-arylation of organophosphorus compounds containing P-H. Using commercially available and inexpensive proline and pipecolinic acid as the ligands greatly improved the efficiency of the coupling reactions, so the method can provide an entry to arylphosphonates, arylphosphinates and arylphosphine oxides.

Alkylation↗
PubMedDate not supplied

[Hydrochlorides of N-hydroxyalkyl-alpha-piperidine carboxylic arylamides possessing antiarrhythmic activity].

It has been demonstrated in experimental arrhythmias of animals (aconitine one in rats, strophanthine in guinea-pigs, creation of an "ectopic focus of excitation" in cats by electric stimulation) that new compounds, the derivatives of piperidine carboxylic acids, possess antiarrhythmic activity. In doses of 6-23 mg/kg, the compounds under study prevented the development of the mixed type arrhythmia induced by intravenous injection of aconitine, prolonged the time of survival and prevented the animals' death during intravenous injection of the arrhythmogenic doses of strophanthine, prolonged the refractory period, and increased the threshold of ventricular fibrillation in cats. As regards the power of the antiarrhythmic effect, the compounds under study--hydrochlorides of arylamides of N-hydroxyalkly-alpha-piperidine carboxylic acids--approach lidocaine, yield to marcaine, and exhibit a broader range of therapeutic action.

Aconitine↗
PubMed2001

Anticoagulation: the present and future.

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect thrombin inhibitors, and coumarins, such as warfarin, which modulate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagatran, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.

Administration, Oral↗
PubMed1992

Effects of intrahippocampal injections of N-methyl-D-aspartate receptor antagonists and scopolamine on working and reference memory assessed in rats by a three-panel runway task.

In order to elucidate the roles of hippocampal N-methyl-D-aspartate-type excitatory amino acid receptors in working and reference memory in rats, the effects of intrahippocampal injections of selective and competitive N-methyl-D-aspartate receptor antagonists such as CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid), 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid and 2-amino-5-phosphonovaleric acid on this behavior were examined with a three-panel runway task. The results were compared with the effect of the muscarinic receptor antagonist scopolamine. In the working memory task, CGS 19755 and 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid at 10 and 32 ng/side, injected bilaterally into the dorsal hippocampus before testing, produced a significant increase in the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points). This also occurred after the rats were given systemic injection of these drugs at 3.2 and 10 mg/kg. In the reference memory task, neither CGS 19755 nor 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid affected the number of errors, whether given at doses up to 32 ng/side intrahippocampally or up to 10 mg/kg systemically. Working memory errors also increased significantly after intrahippocampal injections of d-2-amino-5-phosphonovaleric acid at 100 and 320 ng/side, but were not affected by I-2-amino-5-phosphonovaleric acid at doses up to 1 microgram/side. On the other hand, intrahippocampal scopolamine at 1.0 and 3.2 micrograms/side increased significantly working memory errors, without affecting reference memory errors.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMedDate not supplied

[Retinopathy in Zellweger's cerebrohepatorenal syndrome. The electrophysiological aspects].

There were described recently three biochemical forms of cerebral hepato-renal Zellweger syndrome: hyperpipécolique acidemia; neonatal adrenal leukodystrophy; infantile Refsum malady. These three biochemical forms present similar clinical manifestations. We studied three children with Zellweger (ZS) syndrome at that we established the absence of peroxisomes and an augmentation of pipécolique acid and biliary acids by blood. The children present typical clinical manifestations with retinopathy by pigmented type and ERG with very decreased or abolished amplitude and decreased PEV with prolonged latent time. It is discussed the importance of the constant affection of retinal.

Adrenoleukodystrophy↗
PubMed2006

Pharmacokinetics of cycloalliin, an organosulfur compound found in garlic and onion, in rats.

Cycloalliin, an organosulfur compound found in garlic and onion, has been reported to exert several biological activities and also to remain stable during storage and processing. In this study, we investigated the pharmacokinetics of cycloalliin in rats after intravenous or oral administration. Cycloalliin and its metabolite, (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid, in plasma, urine, feces, and organs was determined by a validated liquid chromatography-mass spectrometry method. When administered intravenously at 50 mg/kg, cycloalliin was rapidly eliminated from blood and excreted into urine, and its total recovery in urine was 97.8% +/- 1.3% in 48 h. After oral administration, cycloalliin appeared rapidly in plasma, with a tmax of 0.47 +/- 0.03 h at 25 mg/kg and 0.67 +/- 0.14 h at 50 mg/kg. Orally administered cycloalliin was distributed in heart, lung, liver, spleen, and especially kidney. The Cmax and AUC0-inf values of cycloalliin at 50 mg/kg were approximately 5 times those at 25 mg/kg. When administered orally at 50 mg/kg, cycloalliin was excreted into urine (17.6% +/- 4.2%) but not feces. However, the total fecal excretion of (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid was 67.3% +/- 5.9% (value corrected for cycloalliin equivalents). In addition, no (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid was detected in plasma (<0.1 microg/mL), and negligible amounts (1.0% +/- 0.3%) were excreted into urine. In in vitro experiments, cycloalliin was reduced to (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid during anaerobic incubation with cecal contents of rats. These data indicated that the low bioavailability (3.73% and 9.65% at 25 and 50 mg/kg, respectively) of cycloalliin was due mainly to reduction to (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid by the intestinal flora and also poor absorption in the upper gastrointestinal tract. These findings are helpful for understanding the biological effects of cycloalliin.

Animals↗
PubMed2007

Sequencing and analysis of the biosynthetic gene cluster of the lipopeptide antibiotic Friulimicin in Actinoplanes friuliensis.

Actinoplanes friuliensis produces the lipopeptide antibiotic friulimicin, which is a cyclic peptide with one exocyclic amino acid linked to a branched-chain fatty acid acyl residue. The structural relationship to daptomycin and the excellent antibacterial performance of friulimicin make the antibiotic an attractive drug candidate. The complete friulimicin biosynthetic gene cluster of 24 open reading frames from A. friuliensis was sequenced and analyzed. In addition to genes for regulation, self-resistance, and transport, the cluster contains genes encoding peptide synthetases, proteins involved in the synthesis and linkage of the fatty acid component of the antibiotic, and proteins involved in the synthesis of the nonproteinogenic amino acids pipecolinic acid, methylaspartic acid, and 2,3-diaminobutyric acid. By using heterologous gene expression in Escherichia coli, we provide biochemical evidence for the stereoselective synthesis of L-pipecolinic acid by the deduced protein of the lysine cyclodeaminase gene pip. Furthermore, we show the involvement of the dabA and dabB genes in the biosynthesis of 2,3-diaminobutyric acid by gene inactivation and subsequent feeding experiments.

Aminobutyrates↗
PubMed1987

Identification and quantification of 5-hydroxypipecolic acid and hydroxyproline in mammalian brain and blood by selected ion monitoring.

A method for the analysis of 5-hydroxypipecolic acid and 4-hydroxyproline in mammalian brain and blood is reported. The identification and quantification of the two hydroxyimino acids were accomplished with gas chromatography/mass spectrometry including a selected ion-monitoring technique following HPLC prepurification. The lower limit of detection for the method is 2 to 10 pmol. The amounts of 5-hydroxypipecolic acid and 4-hydroxyproline in blood were 20 to 30 pmol/ml and 3 to 6 nmol/ml, respectively. Their concentrations in the rabbit whole brain were determined to be 5 and 120 pmol/g, respectively.

Adult↗
PubMedDate not supplied

Enhanced thrombolysis induced by argatroban or activated protein C in the presence or absence of staphylokinase, measured in an in vivo animal model using mesenteric arterioles.

Successful administration of thrombolytic agents is associated with vessel reocclusion in a high proportion of cases. We have previously established an animal model to investigate platelet-rich thrombolytic mechanisms in vivo and demonstrated that recombinant staphylokinase (rSAK)-induced thrombolysis was enhanced by the concomitant administration of the direct thrombin inhibitor argatroban. The present study expanded the use of this model by comparing arterial and venous thrombolysis using advanced image analysis software. Mural thrombi were formed by Helium-Neon laser irradiation in mesenteric arterioles and were shown to be lysed, dose-dependently, by smaller amounts of rSAK than those required in venules. Activated protein C (APC), as well as argatroban, enhanced the rSAK-induced thrombolysis. APC or argatroban also induced thrombolysis in the absence of rSAK, and the effect was inhibited by tranexamic acid. The enhanced thrombolysis induced by APC or argatroban in the presence or absence of rSAK may be due to increased endogenous thrombolysis mediated by the inhibition of thrombin activity or delayed thrombin generation.

Animals↗
PubMed1994

Diphenylhydantoin potentiates the EEG and behavioural effects induced by N-methyl-D-aspartate antagonists in rats.

The N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors are involved in the electrical and behavioural generalization of epileptiform activity within the brain. In rats, both competitive and non-competitive NMDA antagonists induce three dose-dependent stages of EEG patterns: 1) increase in cortical desynchronization periods; 2) increase in amplitude of cortical high frequency (20-30 Hz), low voltage (30-50 microV) background activity; 3) appearance of cortical slow (2-3 Hz) wave-sharp wave complexes. These EEG changes are accompanied by stimulatory-depressive behavioural effects such as stereotypy (circling, head weaving) and ataxia. In the present study, the influence of the prototypic anticonvulsant diphenylhydantoin (DPH) has been tested on the EEG and behavioural effects induced by the non-competitive NMDA antagonists phencyclidine (PCP) and dizocilpine (MK-801) and by the competitive NMDA antagonist cis-4-phosphonomethyl-2-piperidine-carboxylic acid (CGS 19755). Even though DPH (up to 100 mg/kg IP) did not markedly affect basal cortical EEG activity, at doses of 10-100 mg/kg IP it potentiated all the EEG effects induced by the NMDA antagonists. These data support involvement of NMDA neurotransmission in the pharmacological effects of DPH.

Animals↗
PubMed1992

Excitatory amino acids and the actions of cocaine.

Antagonists of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid (EAA) receptors blocked cocaine-induced stereotypy, locomotor stimulation and convulsions. These effects in general appear to involve selectively NMDA type of receptors. The results suggest that NMDA-activated systems are an integral component in the reaction sequences involved in the expression of several behavioral effects of cocaine.

Animals↗
PubMed1980

Association of 6-oxo-piperidine-2-carboxylic acid with penicillin V. Production on Penicillium chrysogenum fermentations.

Analysis of a 13C NMR spectrum of a concentrated broth from Penicillium chrysogenum fermentation revealed the presence of penicillin V and 6-oxo-piperidine-2-carboxylic acid(1) as the principal constituents. The latter lactam, identical to an authentic sample prepared by the cyclization of alpha-aminoadipic acid was present to the extent of 28 mol% of penicillin V. The lactam isolated form the broth was nearly racemic, having a slight excess of the L-isomer. This isolation provides further evidence regarding the biosynthetic precursors of the hydrophobic penicillins.

Carbon Radioisotopes↗
PubMed2000

Synthesis of four stereoisomers of 1,4-thiazane-3-carboxylic acid 1-oxide via the asymmetric transformation (combined isomerization-preferential crystallization) of 1,4-thiazane-3-carboxylic acid.

In order to synthesize four stereoisomers of 1,4-thiazane-3-carboxylic acid 1-oxide (TCA SO), (S)-1,4thiazane-3-carboxylic acid [(S)-TCA], which is one of the precursors, was prepared by the asymmetric transformation (combined isomerization-preferential crystallization) of (RS)-TCA. This asymmetric transformation was used (2R, 3R)-tartaric acid [(R)-TA] as a resolving agent and salicylaldehyde as the epimerization catalyst in propanoic acid at 110 degrees C to afford a salt of (S)-TCA with (R)-TA in 100% de with a yield of over 90%. Optically pure (S)-TCA was obtained by treating the salt with triethylamine in methanol in a yield of over 80%, based on (RS)-TCA as the starting material. In addition, asymmetric transformation of (R)-TCA gave (S)-TCA in a yield of 60-70%. (S)-TCA was oxidized by hydrogen peroxide in dilute hydrochloric acid to selectively crystallize (1S, 3S)-TCA.SO. (1R, 3S)-TCA SO of 70% de from the filtrate was allowed to form a salt with (R)-TA after a treatment with triethylamine to give (1R, 3S)-TCA SO as a single diastereoisomer. (1R, 3R)- and (1S, 3R)-TCA.SO were also prepared by starting from (R)-TCA that had been synthesized from L-cysteine.

Crystallization↗