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F Fülöp

Publications and source records attributed to F Fülöp.

35 records · Page 2Linked to original sources
PubMed2000

Study of diastereomeric thioureas formed with a new chiral derivatizing agent.

(1S,2S)-1,3-Diacetoxy-1-(4-nitrophenyl)-2-propyl isothiocyanate ((S,S)-DANI) was recently introduced as a new chiral derivatizing agent for the enantioseparation of amino compounds. In the present study, diastereomeric derivatives of racemic amino acids were formed with (S,S)-DANI. The thioureas produced were distinguished by means of infrared spectroscopy, theoretical calculations and high-performance liquid chromatography. The differences observed between the corresponding diastereomers by the independent methods are considered to prove the applicability of the new reagent in the field of enantiomer separation.

Amino Acids↗
PubMed1999

Classic preconditioning decreases the harmful accumulation of nitric oxide during ischemia and reperfusion in rat hearts.

BACKGROUND: The role of NO in the mechanism of preconditioning is not understood. Therefore, we studied the effect of preconditioning and subsequent ischemia/reperfusion on myocardial NO content in the presence of an NO synthase (NOS) inhibitor. METHODS AND RESULTS: Isolated working rat hearts were subjected to preconditioning protocols of 3 intermittent periods of rapid pacing or no-flow ischemia of 5 minutes' duration each followed by a test 30 minutes of global no-flow ischemia and 15 minutes of reperfusion. Test ischemia/reperfusion resulted in a deterioration of myocardial function and a considerable increase in cardiac NO content as assessed by electron spin resonance. Preconditioning improved postischemic myocardial function and markedly decreased test ischemia/reperfusion-induced NO accumulation. In the presence of 4.6 micromol/L N(G)-nitro-L-arginine (LNA), basal cardiac NO content decreased significantly, although test ischemia/reperfusion-induced functional deterioration and NO accumulation were not affected in nonpreconditioned hearts. However, the protective effects of preconditioning on both test ischemia/reperfusion-induced functional depression and NO accumulation were abolished. When 4.6 micromol/L LNA was administered after preconditioning, it failed to block the effect of preconditioning. In the presence of 46 micromol/L LNA, ischemia/reperfusion-induced NO accumulation was significantly decreased and postischemic myocardial function was improved in nonpreconditioned hearts. CONCLUSIONS: Our results show that (1) although NO synthesis by the heart is necessary to trigger classic preconditioning, preconditioning in turn attenuates the accumulation of NO during ischemia/reperfusion, and (2) blockade of ischemia/reperfusion-induced accumulation of cardiac NO by preconditioning or by an appropriate concentration of NOS inhibitor alleviates ischemia/reperfusion injury as demonstrated by enhanced postischemic function.

Animals↗
PubMed1999

Synthesis of oxytocin antagonists containing conformationally constrained amino acids in position 2.

Analogues of oxytocin containing D-Trp, 2-amino-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (Atc) or 1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acid (Car) with R or S configurations in position 2 were synthetized, and their receptor bindings were tested on isolated guinea-pig uterus, rat liver and rat kidney inner medulla plasma membranes. The peptides were synthetized in the solid phase by using racemates of Car and Atc. The resulting diastereomeric mixtures were separated by means of RP-HPLC. The binding to the oxytocin receptor was somewhat decreased for the Atc isomers and dramatically decreased for both R- and S-Car, while the D-Trp-containing analogue displayed a relatively high receptor affinity. However, the V1 receptor affinities were almost the same as those of the parent peptide for the Car-containing analogues and dramatically decreased for the S-Atc substituted analogue, which has a relatively high OT/V1 receptor selectivity of 44.5.

Animals↗
PubMed1999

In vivo effects of 2-substituted [Mpa1Sar7Arg8]-oxytocin antagonists on postpartum rat.

A set of oxytocin antagonists consisting of [Mpa1Sar7Arg8]-oxytocin substituted by various conformationally restricted or bulky D amino acids at position 2 were synthetized and biologically tested. In in vivo pharmacological investigations, the effects of these peptides were examined on the spontaneous motor activity of postpartum rat. Three of the newly prepared peptides proved at least as effective in inhibiting uterine contractions as clinically investigated atosiban.

Animals↗
PubMed1999

Direct myocardial anti-ischaemic effect of GTN in both nitrate-tolerant and nontolerant rats: a cyclic GMP-independent activation of KATP.

1. We have recently demonstrated that glyceryl trinitrate (GTN) exerts a direct myocardial anti-ischaemic effect in both GTN-tolerant and nontolerant rats. Here we examined if this effect is mediated by GTN-derived nitric oxide (NO) and involves guanosine 3'5' cyclic monophosphate (cyclic GMP) and ATP-sensitive K+ channels (KATP). 2. Rats were treated with 100 mg kg-1 GTN or vehicle s.c. three times a day for 3 days to induce vascular GTN-tolerance or nontolerance. Isolated working hearts obtained from either GTN-tolerant or nontolerant rats were subjected to 10 min coronary occlusion in the presence of 10-7 M GTN or its solvent. 3. GTN improved myocardial function and reduced lactate dehydrogenase (LDH) release during coronary occlusion in both GTN-tolerant and nontolerant hearts. 4. Cardiac NO content significantly increased after GTN administration in both GTN-tolerant and nontolerant hearts as assessed by electron spin resonance. However, cardiac cyclic GMP content measured by radioimmunoassay was not changed by GTN administration. 5. When hearts from both GTN-tolerant and nontolerant rats were subjected to coronary occlusion in the presence of the KATP-blocker glibenclamide (10-7 M), the drug itself did not affect myocardial function and LDH release, however, it abolished the anti-ischaemic effect of GTN. 6. We conclude that GTN opens KATP via a cyclic GMP-independent mechanism, thereby leading to an anti-ischaemic effect in the heart in both GTN-tolerant and nontolerant rats.

Adenosine Triphosphate↗
PubMed1999

[Lipase-catalyzed resolution of 2-dialkylaminomethylcyclanols. Comparative studies].

Extensive lipase screening was performed in relation to the asymmetric acetylation of rac-2-dialkylaminomethylcyclanols (1-6). The lipase PS- and Novozym 435-catalysed resolutions of 1-6 with various vinyl esters were studied in different organic media. High enantioselectivity (E > 200) was observed when vinyl acetate was used as acylating agent and diethyl ether as solvent. The (1R,2R) enantiomers react preferentially in the case of the cis isomers, whereas the (1R,2S) enantiomers do so in the case of the trans counterparts. The enantioselective acetylation of the five-membered amino alcohols (1, 3 and 5) proceeded much more rapidly than that of the six-membered amino alcohols (2, 4 and 6). The reaction rates were also affected by the solvent and by the quantity of the enzyme.

Acetylation↗
PubMed1999

[Application of ring-chain tautomerism for the development of prodrugs].

Many unfavourable pharmacological and physicochemical properties of drugs can be improved by the application of prodrugs. Ring-chain tautomeric prodrugs include 1,3-X,N-heterocycles prepared from dysfunctional compounds with aldehydes or ketones. From the ring-chain equilibria of these derivatives, the open form undergoes continuous hydrolysis to give the bioactive molecule, which can be either the original dysfunctional compound or an oxo compound. This concept was applied in cases of oxazolidine and thiazolidine prodrugs derived from (-)-ephedrine, L-cysteine and hydrocortisone. From studies on 2-aryl-1,3-X,N-heterocycles, it has been unequivocally concluded that ring-chain tautomerism is characteristic not only for 1,3-O, N-heterocycles, but also for their 1,3-S,N- and 1,3-N,N-analogues. The ratios of the tautomeric forms involved in the equilibria of these systems are strongly influenced by the steric and electronic characters of the substituents. The results demonstrate that the transformation of a drug candidate to a ring-chain tautomeric prodrug is always worthy of consideration, when the pharmacologically active compound contains a 1,2- or 1,3-amino alcohol, a diamine or an amino thiol moiety or an oxo group.

Cysteine↗
PubMed1997

Conformationally constrained deltorphin analogs with 2-aminotetralin-2-carboxylic acid in position 3.

Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorpin analogs with altered hydrophobic and stereoelectronic properties. Deltorphin I and II analogs were synthesized involving the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 2-aminotetralin-2-carboxylic acid (Atc) instead of Phe in the message domain. The peptides were agonists in the subnanomolar range in the MVD assay and in the micromolar or higher range in the GPI assay, showing a very high selectivity for delta receptors. A very similar trend could be observed in radioreceptor binding assays in which selective tritiated opioid ligands were used. (R)- and (S)-Atc-deltoriphins exhibited similar Ki values in the binding assay, with almost complete loss of the stereospecificity of the binding. Conformational studies provided evidence for the little disturbance of the backbone conformational equilibrium when Phe3 is replaced by (S)- or (R)-Atc. The use of the Atc constraint gives additional evidence that, during its interaction with the delta receptor, the side chain of residue 3 adopts the trans conformation at chi 1.

Analgesics, Opioid↗
PubMed1997

Synthesis and opioid binding activity of dermorphin analogues containing cyclic beta-amino acids.

In the present work, eight conformationally constrained analogues of the mu specific opioid peptide dermorphin were synthesized by replacing D-Ala2 with stereoisomers of beta-amino-cycloalkane or cycloalkene carboxylic acids. The resulting peptides were tested for their potency to mu and delta opioid binding sites of rat brain membranes labelled with [3H]Tyr1-D-Ala2-MePhe4-Gly-ol, [3H]DAMGO and [3H]Ile5,6deltorphin, respectively. All of the new derivatives displayed highly attenuated binding to both receptor types, albeit the decrease in their potency seemed to be less in the case of delta binding. Trans position of the beta-amino groups resulted in higher binding affinities than that of the corresponding cis isomers, the latter being more flexible than the former. It is concluded that conformational constraints caused either by a rigid ring structure or cis isomers instead of D-Ala2 in dermorphin-derived peptides are unfavourable for binding activity to either opioid receptors. We propose that interaction of the larger heptapeptide derivatives of dermorphins with the mu receptor is distinct from that of the tetrapeptide morphiceptin.

Amino Acids, Cyclic↗
PubMed1996

[Saturated heterocyclic compounds. 216 (1). Synthesis, structure and ring opening of trans-perhydro-1,4-benzoxazepin-3-one derivatives].

trans-Perhydro-1,4-benzoxazepin-3-ones 2a-e were synthesized and transformed to condensed-skeleton perhydro-trans-1,4-benzoxazepines 3a,b, the thiones 4a,b, the urea derivatives 5a,b, and N-acylated compounds 6a-e. Compounds 6b,d were ring-opened by hydrochloride acid in ethanol to yield trans-2 (1-carbethoxyethoxy)-1-(acylaminomethyl)-cyclohexane derivatives 7b,d. The 1H- and 13C-nmr investigation and X-ray analysis of 5b and 6c,d proved that the expected N-acylated derivatives were formed and that both rings of the annolated compounds have a chair conformation.

Acetylation↗
PubMed1994

[Synthesis of tert-butylcyclopentane-fused 1,3-oxazines and 1,3-thiazines].

Chlorosulphonyl isocyanate (CSI) addition to 4-tert-butylcyclopentene furnished the azetidinone (3) in a stereospecific reaction. Azetidinone 3 was transformed by ring opening esterification and lithium aluminium hydride (LAH) reduction to the 2-hydroxy-methyl-4-tert-butyl-1-cyclopentylamine (6). The N-methyl-aminoalcohol (8) was prepared from amino esters (5) with ethyl chloroformate and subsequent LAH reduction. By different ring-closure methods, a number of tert-butyl-cyclopentante-fused 1,3-oxazines and 1,3-thiazines were synthesized. A comparative study of the prepared compounds was performed by IR, 1H- and 13C-NMR, DEPT and DNOE measurements.

Indicators and Reagents↗
PubMed1983

[Synthesis, conformation and pharmacological effect of some stereoisomeric condensed 1,3-oxazine-4-ones. 44: Stereochemical studies; 22: Saturated heterocycles].

It has been reported the synthesis, examination of the stereochemistry and biological effect of 2-substituted-cis-5,6-trimethylen-, cis- and trans-5,6-tetramethylene and -5,6-pentamethylene-2,3,5,6-tetrahydro-1,3-oxazine-4-one derivatives. Primarily cis-isomers were synthetized because in the pharmacological test systems the trans isomers were less active. The compounds tested have an antiphlogistic effect of different intrinsic activity.

Animals↗
PubMedDate not supplied

An operated case of Holt-Oram syndrome with autosomal dominant inheritance.

This report is concerned with a patient successfully operated for Holt-Oram syndrome. The disorder is inherited dominantly with complete penetrance and variable expressivity. It is pointed out that in cases of congenital heart disease familial cumulation must be borne in mind which can easily be verified by pedigree investigation. After demonstrating autosomal dominant inheritance, suitable inferences must be drawn for genetic counseling. Attention is drawn to the heart-surgical significance of the rhythm disorders so often associated with the syndrome.

Abnormalities, Multiple↗
PubMedDate not supplied

[High performance liquid chromatographic enantiomer separation of beta-blocking agents with a new isothiocyanate type chiral derivatizing agent].

The applicability of (1R,2R)-1,3-diacetoxy-1-(4-nitrophenyl)-2-propyl isothiocyanate [(R,R)-DANI] as a recently developed chiral derivatizing agent for the enantioseparation of a series of beta-blockers is described. The thiourea diastereomers formed were analysed by reversed-phase high-performance liquid chromatography, mixtures of water and methanol or acetonitrile being used for elution. Conditions of derivatizations (temperature, reagent excess and reaction time) were optimized. The effects of organic modifiers on the retention and separation were investigated; the diastereomers could readily be baseline-separated with methanol-containing mobile phases. The reagent allowed the detection of all four stereoisomers of labetalol, which has two chiral centres.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

[Synthesis and in vitro receptor analysis of new potential oxytocin antagonists].

Oxytocin (OT) itself and the sensitivity of the uterus to OT play a crucial role in the initiation of both normal and pathologically early delivery. It recognition of the complex mechanism of action suggests that specific OT antagonists are of therapeutic value in postponing early contractions. In this study neurohypophyseal hormone analogues containing Sar in position 7, Arg in position 8, and various conformationally restricted or bulky derivatives of phenilalanine and tryptophan amino acids in position 2 were prepared to design more potent and selective OT antagonists. We determined the ligand-receptor binding characteristics of these newly synthetized peptides in the presence of [3H]oxytocin and [3H]vasopressin on isolated guinea-pig uterus, rat liver and kidney inner medulla plasma membranes. In the case of each peptides we calculated the Ki values and the selectivity ratio. The binding to the OT receptor was dramatically decreased for the Trp-derivatives containing analogues, while the Phe-derivatives containing analogues displayed a relatively high receptor affinity and have a relatively high OT/VP1 receptor selectivity.

Amino Acid Substitution↗