Biomedical subjects

B Noszál

Publications and source records attributed to B Noszál.

At least 19 recordsLinked to original sources

PubMed2006

Site-specific acid-base properties of pholcodine and related compounds.

The acid-base properties of pholcodine, a cough-depressant agent, and related compounds including metabolites were studied by 1H NMR-pH titrations, and are characterised in terms of macroscopic and microscopic protonation constants. New N-methylated derivatives were also synthesized in order to quantitate site- and nucleus-specific protonation shifts and to unravel microscopic acid-base equilibria. The piperidine nitrogen was found to be 38 and 400 times more basic than its morpholine counterpart in pholcodine and norpholcodine, respectively. The protonation data show that the molecule of pholcodine bears an average of positive charge of 1.07 at physiological pH, preventing it from entering the central nervous system, a plausible reason for its lack of analgesic or addictive properties. The protonation constants of pholcodine and its derivatives are interpreted by comparing with related molecules of pharmaceutical interest. The pH-dependent relative concentrations of the variously protonated forms of pholcodine and morphine are depicted in distribution diagrams.

Acids↗

PubMed2001

Enhancing effect of zinc on astroglial and cerebral endothelial histamine uptake.

We have studied the effect of zinc ion on the uptake of histamine (HA) into cultured astroglial and cerebral endothelial cells and established that Zn(2+) enhances the uptake of the amine dose-dependently and in remarkable extents by increasing the V(max) to about 3-fold (from 3.25 +/- 0.42 to 8.50 +/- 0.97 pmol/mg protein/min in astroglial cells) without altering the K(M) (0.20 +/- 0.03 microM) significantly. The stimulatory effect of zinc ion showed strong sensitivity for VUF 8407, an inhibitory compound of astroglial and cerebral endothelial uptake of HA. In the presence of 20 microM VUF 8407 the zinc-enhanced uptake was reduced by about 50% in both cell types. Binding measurements revealed increased capacities of the zinc-exposed HA binding (B(max)= 0.41 +/- 0.05 increased to 1.21 +/- 0.16 pmol/mg protein in astroglial membranes and B(max) = 0.25 +/- 0.03 enhanced to 1.05 +/- 0.12 pmol/mg protein in cerebral endothelial membranes) but statistically unchanged affinity of the ligand for HA carrier (K(D) values calculated as 35.2 +/- 3.4 nM and 45.1 +/- 3.8 nM for astroglial bindings; whereas 25 +/- 2.1 nM and 30 +/- 2.6 nM for cerebral endothelial bindings of the amine). The compound VUF 8407 reduced the B(max) of zinc-exposed HA binding of astroglial membranes but did not modify the K(D) of the zinc-exposed membrane significantly. The ex vivo experiments confirmed our in vitro findings; an i.c.v. dose of 0.4 micromol/kg ZnSO(4,) 24 hr after the injection, enhanced the uptake of [(3)H]HA into dissociated hypothalamic and cerebellar cells to about 2- and 3-fold, respectively. Present data clearly showed that zinc exposures enhance the astroglial and the cerebral endothelial uptake of HA in vitro and it might be considered that zinc produces similar effects in vivo. Free zinc may participate in the regulation of the extraneuronal HA concentration and this metal ion (endogenous or exogenous) might be favored in the removal of the amine from the interstitial space especially in conditions with relatively high HA.

Animals↗

PubMed2001

[Synthesis of carboline alkaloid analogues].

Hybrid compounds were synthesized combining the structural features of two isomer natural indolalkaloids rutaecarpine (1) and nauclefine (2). These aza-bioisosteric analogues are the first representatives of a new heterocyclic ring system. Two alternative reaction routes were developed for the synthesis of pentacyclic compounds (4, 5) in which the key step is the Fischer indolization of the 6-phenylhydrazono-dipyrido[1,2-a;4,3-d]pirimidine-11-ones. In the case of E-ring substituted derivatives the synthesis was carried out via preparation and chemical transformation of pyrido[1,2-a]pirimidine-4-ones (14, 15) to 2-substituted-3-aza-rutaecarpines (17-20). Finally, the nucleophilic displacement of the chlorine atom of 2-chloro-3-aza-rutaecarpine (18) by dialkylaminoethylamine provided the 2-amino-substituted derivative (20) having improved physico-chemical properties and increased antitumour activity. The new compounds are characterized by UV, IR, 1H, 13C NMR spectroscopy.

Alkaloids↗

PubMed2001

[Use of crystal conversion reactions in the synthesis of pentacyclic alkaloid analogues].

During investigation of substitution of debenzorutaecarpine derivatives thermal cyclization reactions was observed to produce new fused heterocyclic systems. The optimal temperature of cyclizations was determined by differential calorimetric measurements of crystals of intermediate products. The thermolysis of 2-azido-3-formil-debenzorutaecarpine gave, after elimination nitrogen, izooxazolo-debenzorutaecarpine in good yield. The cyclization of the 2-azido-3-nitroso-debenzorutaecarpine readily led to oxadiazolo E-ring analogue of rutaecarpine. The thermal cyclization of 2-hydroxy-debenzorutaecarpines gave 2-oxo- and 4-oxo-pyrano E-ring analogues of rutaecarpine. The structure of substances was confirmed by spectroscopic methods. The synthesised compounds are considered as first representatives of new heterocyclic ring systems.

Alkaloids↗

PubMed2000

Population, acid-base, and redox properties of N-acetylcysteine conformers.

Rotamers of N-acetyl-L-cysteine (NAC, the most popular mucolytic drug) are characterized in terms of populations, site- and conformer-specific acid-base properties, reducing strength, and molecular pharmacology. A new, general relationship between the bulk- and rotamer-specific basicities is introduced. NAC at high pH predominantly exists in a trans thiolate-carboxylate rotameric form, whereas protonation promotes the occurrence of intramolecular hydrogen bond-forming isomers. Distribution curves of the rotamers are depicted as a function of pH. Rotamer-dependent thiolate basicities differ by up to 0.5 log k units. Carboxylate basicities show slight conformation-dependence only. The membrane-penetrating capabilities from various compartments of the body are assessed on the basis of the pH-dependent charge of the molecule. The thiol-disulfide half-cell potential is calculated, using the correlation between the thiolate basicity and oxidizability. The oxidation-reduction properties of NAC are compared to those of other biological thiols in their definite microscopic forms. The pharmacokinetic behavior is interpreted in terms of the physicochemical parameters, providing molecular/submolecular explanation for several therapeutic properties of NAC.

Acetylcysteine↗

PubMed2000

Capillary electrophoresis separation of vinpocetine and related compounds: prediction of electrophoretic mobilities in partly aqueous media.

Offord's equation, a relationship between electrophoretic mobility and charge, size and shape of peptides, has been extended to quantitate the electrophoretic mobility of vinca alkaloids. Partly aqueous protonation constants and the derived theoretical mobilities have been proven to be able to predict experimental electrophoretic mobilities. In practice, seven vincamine derivatives of very low water-solubility were separated by capillary electrophoresis. Buffer total concentration, apparent pH and methanol content, the three most important parameters of the running buffer, were used in triangular resolution mapping to characterize separation. Even though electrophoresis is well known to slow down in partly aqueous media, under our optimized circumstances a baseline separation was achieved within 8 min in each case.

Electrophoresis, Capillary↗

PubMed2000

Deconvolution of composite chromatographic peaks by simultaneous dual detections.

Composite chromatographic peaks are deconvoluted by a method that uses ratio formation from signals of simultaneous double detection. The method is generally suitable if two detector signals can simultaneously be acquired and their uses do not need any a priori assumption or mathematical shape analysis. A simple deduction makes the compound- and detector-specific intensive parameters explicit, which allows for the digital construction of directly invisible component peaks. The simultaneous double detection is shown to be superior to coupled detectors, sequentially fixed chromatograms, and subsequently synchronized peaks. The combination of circular dichroism and ultraviolet (UV) detection is shown to be especially advantageous in the analysis of enantiomers for which the other ratio-forming peak-deconvolution techniques have inherently been insensitive. The double chiroptical UV detection can be of further use to decompose overlapping peaks of nonenantiomeric compounds that are highly similar. The capacity of the method is exemplified by the analysis of morphine alkaloids, steroid oximes, and synthetic heterocycles.

Chromatography, Liquid↗

PubMed1999

Characterization of potential NMDA and cholecystokinin antagonists I. acid-base properties of 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxylic acids at the molecular and submolecular levels.

The protonation macroconstants (log K) of 4(3H)-quinazolone (1) and two 2-methyl-4-oxo-3H-alkyl-quinazoline-3-carboxylic acid derivatives (2,3) were determined by pH-potentiometry. The acid-base chemistry of compounds 2 and 3, where proton-bindings take place in an overlapping fashion, was described in terms of protonation microconstants as well. Microspeciation was carried out by two means: UV-pH titration (selective, pH-dependent monitoring of the N1-binding site), and deductively (using a derivative compound as covalently fixed model of one of the protonation isomers). The microconstant values obtained by the two different methods are in agreement within 0.05 log K units. Microspeciation revealed remarkable differences between the two homologue compounds (2 and 3). The microconstant values show that insertion of a second methylene moiety into the aliphatic acid side-chain (1) increases the electron-density and most basicity parameters of both functional groups; (2) significantly modifies the extent of site-site interactions in the molecule; (3) opens new conformational preferences by N1 ring nitrogen-carboxylic group intramolecular hydrogen bond formation and (4) reverses the predominantly zwitterion-involved protonation pathway into a neutral form-involved pathway. These molecules exemplify that microconstant values allow the comparative prediction and quantitative evaluation of pharmacokinetic behaviour, and signify the fact that microspeciation is a powerful tool in the process of drug development.

Cholecystokinin↗

PubMed1999

Proton speciation and microspeciation of vinpocetine and related compounds in aqueous and biomimetic media.

PURPOSE: The determination of protonation macroconstants of twelve compounds in the vincamine drug family and the determination of protonation microconstants of cis- and trans-apovincaminic acid in media of various solvent composition to characterise their site-specific basicity and to estimate the concentration of the membrane-penetrating and receptor-binding forms. METHODS: UV-pH titrations have been used to determine the protonation macroconstants in 10-43 wt% methanol/water mixtures. Yasuda-Shedlovsky extrapolation was applied to obtain aqueous logK values for compounds sparingly soluble in water. Protonation microconstants were also determined by deductive methods for compounds of free carboxylic group. RESULTS: In the case of the two water-soluble compounds the extrapolated and the directly measured aqueous logK values were in good agreement, verifying all other extrapolated data. Compounds of cis-D/E ring anellation are 0.4-0.8 logK units more basic than their epimeric, trans counterparts. The pH-dependent distribution of apovin-caminic acid microspecies in aqueous and membrane-like media is depicted in microspeciation diagrams. CONCLUSIONS: The N(4) nitrogen is more shielded by the adjacent ethyl group in trans-D/E ring anellation eburnanes than in cis ones, as reflected by the protonation constants. Solvent-dependent basicity data predict superiority of trans isomers in lipophilicity and membrane-penetrating ability.

Hydrogen-Ion Concentration↗

PubMed1999

[Characterization of drug, narcotic and psychotropic drug chirality by statistical methods].

The percentage of chiral entities among drug, narcotic drug and psychotropic compounds is steadily increasing. Receptors of the human body recognize the enantiomeric forms of constitutionally identical compounds as entirely different chemical agents. Based upon these facts, this paper reports the percentage of chiral compounds in the various pharmacological classes, and related data. Pertinent terms, such as eutomer, distomer, eudismic index, eudismic affinity quotient are defined. Differences in biological activity between eutomers and distomers are exemplified. The pharmacological classes and subclasses of highest chirality, and the "most chiral" active principles are shown. Some puzzling observations on pharmacological behaviour of stereoisomers are highlighted. The necessity of "racemate switch" in the pharmaceutical industry, and the significance of stereo-specific interactions between the drug, narcotic drug and psychotropic ligands, and complementary, "pocket" moieties of the human body are emphasized. Some features of enantiopharmacology, a fledgling science in the interface of stereochemistry and traditional pharmacology are introduced. The statistical treatment of asymmetric compounds in pharmacological classes and subclasses shows that presently, the percentage of chirality in drug categories is more characteristic of the origin of the compound than its target molecule.

Humans↗

PubMed1999

[Microequilibrium of drug molecules].

Protonation macro-, micro-, and submicro constants are physico-chemical parameters of crucial importance, concerning the fate of bio-, drug, and narcotic drug molecules in the body and in protic solvents. The most important characteristics, relationships, applications and biological significance of these parameters are reviewed, using acetylcysteine and cysteine, as examples. The mucolytic effect of acetylcysteine, an active principle in numerous drugs, is interpreted in terms of protonation state of the molecule and its thiolate site. Microscopic protonation constants of acetylcysteine, data that have not previously appeared, are also reported.

Acetylcysteine↗

PubMed1999

[Preparation and characterization of potential antineoplastic agents].

A parallel combinatorial library of over sixteen hundred compounds has been designed and synthesized for the development of new potential peptidomimetic protein tyrosine kinase (PTK) inhibitor leads that is aimed for intervening with the substrate binding site of the pp60c-src enzyme. The new structures were based on known PTK inhibitors having at least two variously substituted aromatic moieties attached by spacer groups of different length and flexibility. Eleven bis-aryl type inhibitory compounds were found in the range of 18-100 micromolar IC50 concentrations from combinations of twelve different substituents. Molecular modeling of the active compounds showed a characteristic distance of 13-14 A between the farthest sp2 carbon atoms of the two aromatic rings. Conformational analysis of several peptide substrates recently found for pp60c-src PTK [5,6,7] showed that the energy minimized conformers had the same distance between two aromatic moieties. Several compounds in the library not only showed remarkable PTK inhibitory activity but also a significant apoptosis inducing effect on HT-29 human colon tumor cells.

Antineoplastic Agents↗

PubMed1999

[Novel chiroptical methods in pharmaceutical analysis].

Chiroptical spectroscopy, and its double and triple hyphenated combinations with UV-VIS spectroscopy and/or separation techniques constitute great progress in pharmaceutical analysis, of which five recently developed methods are surveyed here, as follows: The determination of enantiomeric purity by double, CD/UV detection without, and with the latter one provides enhanced sensitivity and selectivity. The determination of chromatographic peak homogeneity, by double detection, and peak slicing by recording. The separation, identification and four stereoisomers of doubly chiral compounds, by HPLC separation on chiral column, and optical-chiroptical detection.

Chromatography, High Pressure Liquid↗

PubMed1999

[Characterization of the kinetics of ester hydrolysis at the submolecular level].

Ester-type compounds are important drugs as directly binding active principles, but also, as prodrugs that provide the acting agent after hydrolytic decomposition. The profound characterisation of the kinetics of ester hydrolysis is therefore equally important to interpret and design metabolic processes and prodrug-->drug transitions. The extramolecular factors (temperature, ionic strength, solvent etc.) influencing the rate constant values have extensively been studied. Contrary to that, few data can be found on the effect and magnitude of the intramolecular factors (substituent effect, neighbour-group protonation). This paper reports the introduction and determination of microscopic rate constants of ester hydrolysis, a new physicochemical parameter, which is defined in the sense of the protonation state of the basic site(s) adjacent the ester group. The microscopic rate constants of phenylalanine-methyl-ester hydrolysis are determined and interpreted. Also, the principles to characterise the rate of monobasic double esters at the submolecular level, exemplified by cocaine, are established.

Esters↗

PubMed1999

[Stereochemical aspects of narcotic and psychotropic drug action].

Medicinal drugs are predominantly, whereas narcotic and psychotropic drugs are exclusively exogenous compounds. Three further fundamental properties of the narcotic/psychotropic compounds of significant abuse potential is that they all are of natural (plant or microbial) origin, they contain a large number of chiral atoms, and they influence the neurotransmission processes in the central nervous system. For some of them, the existence of corresponding endogenous ligands have recently been reported. Since exogenous compounds and their endogenous ligands are assumed to bind the same target moiety of the receptor, several fundamental questions arise: To what extent can stereochemical relationships be established between the exogenous compound and its endogenous counterpart? Do they have superimposable moieties? Are the corresponding chiral atoms of the same configuration? Is there a chiral-genetic relationship between the exogenous and endogenous compound? Theoretical aspects and answers to all these questions are sought for morphine, cocaine, LSD, tetrahydrocannabinol, amphetamine and related molecules.

Analgesics, Opioid↗

PubMed1999

[Synthesis and investigation of protonation properties and lipophilicity of some new quinazolone-3-carboxylic acid derivatives].

Several new quinazolone-carboxylic acid derivatives as potential NMDA and AMPA receptor antagonists have been synthesized, and the protonation properties and lipophilicity of some representative molecules have also been studied. The protonation macroconstants (logK) of 4(3H)-quinazolone (Q0) and two 2-methyl-4-oxo-3H-quinazoline-3-carboxylic acids (Q1, Q2) were determined by pH-potentiometry. The acid-base chemistry of Q1 and Q2, where protein-bindings take place in an overlapping fashion, was described in terms of protonation microconstants (logk) as well. Microspeciation was carried out by UV-pH titration and deductive method. Microspeciation revealed remarkable differences between the two homologue compounds (Q1 and Q2), namely insertion of a second methylene moiety into the aliphatic acid side-chain reversed the predominantly zwitterion-involved protonation pathway into neutral form-involved one. Lipophilicity of our molecules was described by the octanol-water partition coefficients. The apparent partition coefficients of Q1 and Q2 were determined by shake-flask method and converted into true logP values using the protonation microconstants. The unexpected differences between their true logP values were explained, similarly to the different protonation pathways with conformational preferences and formation of intramolecular interactions. Out of the other 15 monoprotic quinazolone compounds the lipophilicity of 10 molecules (Q8-Q17, experimental set) was determined by RP-TLC method with the help of a calibration set consisting of 12 standard molecules, five quinazolones (Q3-Q7, determined by shake-flask method) and seven pyrido[1,2a]pyrimidines (PP1-PP7). The obtained logP values proved mostly the expected structure-property relationships. These physico-chemical investigations are pieces of predictive information for the pharmacokinetics of our compounds. These are also discussed in the paper.

Carboxylic Acids↗

PubMed1998

Characterization of calcified deposits on contraceptive intrauterine devices.

The formation of calcified deposits on > 200 contraceptive intrauterine devices (IUD) was quantitated as a function of time in healthy women, pregnant women, and women with a pathologic lesion. The incrustment formation was significantly enhanced when inflammation occurred, but change could not be observed in cases of pregnancy. The incrustments were analyzed by x-ray diffraction, infrared spectroscopy, x-ray microprobe, and ultramicrochemical stone analysis techniques. Major components and their average w/w percent quantities in the incrustments are as follows: calcium carbonate 75%, apatite 5%, and organic matrix 20%. Earlier hypotheses on the chemical processes of deposit formation are discussed, and a new, ionic mechanism of calcification on IUD surfaces is suggested.

Calcinosis↗

PubMed1998

[Determination of enantiomeric purity by simultaneous dual circular dichroism and ultraviolet spectrophotometry].

A method is described for the determination of enantiomeric composition. The ellipticity and absorbances of the sample are measured simultaneously by CD and UV spectroscopies, and the resulting G value is determined. G is an intensive physico-chemical parameter, a close derivative of anisotropy factor. Its magnitude is identical with opposite sign for enantiomers. The experimental G value is concentration-independent, as long as both absorption and ellipticity are linear functions of concentration. The analytical procedure introduced here is simple, rapid, and inexpensive, even though it includes calibration with standards of established enantiomeric composition. Provided the sample contains some UV-active contaminant(s), the method can be used after achiral chromatographic purification. By virtue, the method lacks several sources of error, arising normally from concentration inaccuracies. Applicability of the principles is tested by the example of phenylglycine and mandelic acid. Advantages of the method allowed the determination of phenylglycine enantiomer purity with an accuracy of 0.1%.

Calibration↗