Dimorphism of 3-methyl-5-ethyl-5-phenylimidazolidinedione-2,4.
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Anticonvulsants↗
Biomedical subjects
R Kaliszan
Publications and source records attributed to R Kaliszan.
Scientific communication. Bimorphism of urea derivatives.
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Isomerism↗
Determination of 5-allilo-5-(2'-hydroxypropyl)-barbituric acid in decomposed solutions.
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1-Propanol↗
Collagen immobilised on silica derivatives as a new stationary phase for HPLC.
Synthesis of new stationary phases containing covalently bound collagen has been described. Commercially available soluble collagen and the silica derivatives, aminopropylsilica (APS) and diol-silica, were used for the experiment. The products of synthesis were subjected to elemental analysis and to a 13C-NMR analysis to prove the presence of the covalently bound protein on the support's surface. The stationary phases were packed into the columns and introduced into an HPLC system. A series of diversified test compounds was analysed to elucidate the retention mechanism operating on the collagen column by means of the quantitative structure-retention relationship (QSRR) analysis. Chromatographic analysis of a series of selected compounds was performed for which human skin permeation data were available. Quantitative structure-activity relationship (QSAR) analysis was done to model the human skin permeation by employing of the chromatographic data determined on the collagen column. The newly obtained collagen phases were demonstrated to possess distinctive retention properties due to a combination of specific (polar) and hydrophobic solute-stationary phase interactions. The normal-phase retention mechanism seemed to prevail on the collagen phases. For the set of test solutes available the interactions with collagen appear to be of secondary importance for their ability to permeate human skin compared to their hydrophobicity and binding to keratin. None the less, the collagen columns may be of value to complete the chromatographic model of human skin permeation.
Chromatography, High Pressure Liquid↗
Quantitative relationships between the structure of beta-adrenolytic and antihistamine drugs and their retention on an alpha 1-acid glycoprotein HPLC column.
Chromatographic retention parameters of a series of 7 beta-adrenolytics and of 12 antihistamine drugs were determined employing an alpha 1-acid glycoprotein (AGP) high-performance liquid chromatographic (HPLC) column. For the group of antihistamines capillary electrophoretic (CE) retention was additionally measured in the presence of either AGP or human serum albumin (HSA). Two series of solutes hydrophobicity parameters were obtained by reversed-phase HPLC on an immobilized artificial membrane (IAM) column. The solutes studied were subjected to molecular modelling and the structural descriptors obtained were applied in studies of quantitative structure-retention (protein binding) relationships (QSRR). It was found that retention on AGP correlates well with the literature on physiological protein binding data. This retention was demonstrated to depend on hydrophobicity: to a lesser extent in the case of beta-adrenolytics and strongly in the case of antihistamines. Hydrophobicity, along with molecular width and electron excess charge on aliphatic nitrogen was demonstrated to describe retention of antihistamines on AGP. The AGP column is recommended as a convenient reactor for studies of drug-protein interactions. Preliminary CE data do not correlate with the HPLC data.
Adrenergic beta-Antagonists↗
Binding site for basic drugs on alpha 1-acid glycoprotein as revealed by chemometric analysis of biochromatographic data.
Interactions between alpha 1-acid glycoprotein (AGP) and 52 basic drugs were quantified by means of high-performance liquid chromatography (HPLC). The HPLC retention parameters were related quantitatively to the hydrophobicity and molecular modelling parameters, giving rise to the prediction of relative drug-AGP binding from the chemical structure of a drug. A structural model of one binding site on AGP, common for various classes of drugs, was defined which accounted for the observed and reported differences in binding to AGP. A combination of biochromatography and chemometrics has been presented as a promising new approach in biochemical/pharmacological studies.
Binding Sites↗
Chromatographic modelling of interactions between melanin and phenothiazine and dibenzazepine drugs.
Differences in drug-melanin interactions were determined for 13 phenothiazine neuroleptics and 2 dibenzazepine thymoleptics by means of high-performance liquid chromatography. The chromatographic column was packed with a stationary phase obtained by chemical immobilization of synthetic L-dopa melanin on silica particles. For six phenothiazines the melanin-binding parameters were also determined by an ultrafiltration method. Correlation between measures of drug-melanin interaction determined chromatographically and by the standard slow-equilibrium method was significant, however moderate. The chromatographic method of assessing interactions between drugs and melanin permitted reliable and quantitatively comparable data for representative series of solutes to be readily obtained. Such data were subjected to the analysis of quantitative structure-retention relationships (QSRR). It was found that retention of the agents on the immobilized melanin column could be described by two-parameter regression equations comprising the energy of the lowest unoccupied molecular orbital and either the water-accessible surface area of a drug molecule or its hydrophobicity parameter, determined chromatographically on an immobilized artificial membrane column. The QSRR equation derived allows for the estimation of melanin binding based on the structure of a compound candidate, and thus rationalizes predictions of potential toxicity of drugs or drug candidates.
Antidepressive Agents↗
New antagonists of the vasopressin receptor mediated contraction in rat tail artery.
A perfused isolated rat tail artery preparation was employed to study antagonistic properties of four newly synthesized arginine-vasopressin (AVP) analogues against the V1 receptor. The activity of the agents SCATyr(Me)AVP, OCATyr(Me)AVP, OCAAVP and SCAAVP was related to that of a recognized antagonist d(CH2)5Tyr(Me)AVP. SCATyr(Me)AVP elicited outstanding antagonistic properties by blocking at concentration of 10(-7) M nearly completely the constrictory activity of AVP. At concentration of 10(-9) M the agent inhibited the AVP-induced constriction of artery about 40 times more effectively than the oxytocin (OXT)-induced constriction. The results obtained prove the validity of the structure-activity relationship based search for new potent V1 receptor antagonists.
Angiotensin Receptor Antagonists↗
Comparative study of antithrombotic and antiaggregatory activity of acetylsalicylic acid, ticlopidine and a new noncarboxylic acid antiinflammatory pyrazine derivative HF90.
The action of acetylsalicylic acid, ticlopidine and a new pyrazine derivative HF90 selected in preliminary screenings (11, 18, 19) was studied by using the mouse antithrombotic assay according to DiMinno and Silver (22) and in vitro blood platelet aggregation method according to Born (23). Acute pulmonary thromboembolism was induced by injection of a mixture of collagen and epinephrine into the mouse tail vein. The effect of HF90, an acidic pyrazine derivative possessing active methylene moiety, administered at doses of 50 and 100 mg/kg, was compared to the action of the well established antithrombotic agents: ticlopidine (100 mg/kg) and acetylsalicylic acid (20 mg/kg). The compounds were administered i.p. in single doses 1 h and 24 h before the thrombotic challenge or once a day per three consecutive days before the thrombotic challenge. Ticlopidine appeared to provide the better protection against microembolism than acetylsalicylic acid although its effect has not manifested itself immediately after administration. The pyrazine derivative examined has a lower but significant antithrombotic activity. The chemical class of pyrazine derivatives with active methylene moiety (the so called pyrazine CH/NH-acids) (16) provides a new original antiinflammatory pharmacophore and HF90 may serve as the "lead compound" in the search for new agents of pharmacological interest.
Animals↗
Estimation of buspirone-bovine serum albumin binding by affinity capillary electrophoresis.
Drug-protein binding is an important process in pharmacokinetic phase of drug action. Capillary electrophoresis was employed, specifically the Hummel-Dreyer method and Scatchard analysis, to study the interactions of an anxiolytic drug, buspirone, with pure bovine serum albumin (BSA) and with BSA present in the human recombinant 5-HT(1A) serotonin receptor preparation. The binding constant of buspirone with BSA determined in free BSA solution was K = 5.55 x 10(4) M(-1) whereas its value with BSA present in the serotonin receptor preparation was K = 5.57 x 10(4) M(-1). The method was found to be inadequate for measuring the specific binding interactions between buspirone and the 5-HT(1A) receptor in the preparation employed.
Animals↗
High performance liquid chromatographic (HPLC) measures of hydrophobicity as determined by means of new HPLC columns.
Two new commercially available reversed phase high performance liquid chromatographic (HPLC) columns were tested from the view point of their usefulness for determination of hydrophobicity by means of partition chromatography. One column comprised a specially prepared hydrocarbon-bonded silica stationary phase material. The other column was packed with a polybutadiene-coated alumina (PBCA) phase. As reference served a regular commercial octadecylsilica (ODS) column. A series of test solutes were pyrazine CH- and NH-acids--the compounds which are able to take part in specific as well as in nonspecific intermolecular interactions. Unique properties of the new hydrocarbonaceous column manifested themselves in regular linear relationships between logarithms of capacity factors and volume percent of methanol in aqueous eluent. The main advantage of the PBCA column is a possibility of performing chromatography at alkaline pH. Both new columns are superior to regular ODS columns in respect of providing reliable chromatographic measures of hydrophobicity. It was observed that hydrophobicity parameters determined in individual HPLC systems are not highly intercorrelated and hence can reflect different structural features of solutes.
Aluminum↗
IR analysis of crystalline samples of some urea derivatives.
The dependence of an IR spectrum of crystal samples of allantoin, barbital, chloroethylaminouracil (dopan), carbromal, 5-allyl-5-(beta-hydroxypropyl)-barbituric acid (ipronal) and theophyllin upon the method of crystals preparation was found after 3 months storage of crystals. There were no differences in the case of mephenytoin. The results obtained here demonstrate the possibility of an occurence of the majority of the analyzed substances as metastable polymorphic modifications in solid dosage forms. Furthermore, the IR identification of drugs requires crystallization of a substance from a particular solvent just before analysis.
Allantoin↗
Quantitative relationships between hydrophobicity and hypotensive activity of diazacycloalkane derivatives.
The effect of a series of ten newly synthesized diazacycloalkanes as well as four standard imidazoline drugs on blood pressure of anesthetized normotensive rats was measured. The hypotensive activity of the agents studied, expressed as logit of the maximum effect, logit E(%), was quantitatively related to the changes in their chemical structure. Highly significant relationship between the hydrophobicity parameter, sigma f, and logit E(%) value has been found.
Animals↗
A search for new antihypertensive agents. I. Alpha-adrenergic activity and selection of structures among pyrazine substituted imidazolines.
A group of new pyrazinylimidazolines was prepared and their effect on the contraction of isolated rat tail artery as well as their effect on blood pressure in urethane anesthetized normotensive rats were tested. The biological responses were compared to those elicited by standard imidazoline drugs and structure-activity relationships were analysed. The new chemical derivatives were subsequently synthetized and tested pharmacologically. Basing on the experimental results obtained and comparing these to the reported data on arylimidazolines the following suggestions have been put forward concerning the further modifications of alpha-adrenergically active pyrazinylimidazolines: 1) a distance of about 5 A should separate imidazoline nitrogen and pyrazine nucleus, 2) bond refractivity of the separating bridge should be above 5.33, 3) hydrophobicity of substituents in pyrazine ring must be possibly high.
Animals↗
A search for new antihypertensive agents. II. Circulatory activity and selection of structures among 2-methylbenzimidazole derivatives.
A series of twelve 2-methylbenzimidazole derivatives was prepared and their effect on the contraction of isolated rat tail artery, on beating rate and amplitude of isolated rat heart atria, on human blood platelet aggregation, and on blood pressure in urethane-anesthetized normotensive rats were tested. Numerical measures of pharmacodynamic activity were quantitatively related to the changes in chemical structure of the agents. Conclusions are drawn about the mechanism of pharmacodynamic action of 2-methylbenzimidazole derivatives, which is not executed directly through the adrenergic system. The further direction of synthesis is established basing on the results obtained.
Animals↗
Dimorphism of ureides. alpha-Bromisovalerylurea (bromisoval) and alpha-bromdiaethylacetylcarbamide (carbromal).
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Bromine↗
A method of evaluation of quality of 4-methyl-5-(bis-(beta-chloroethyl)-amino)-uracil.
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Drug Stability↗
Studies on the quantitative structure-activity relationships in pyrazine carbothioamide derivatives.
Quantitative relationships were studied between tuberculostatic potency in vitro and structure parameters of pyrazine carbothioamides. The activity of the compounds was found to be dependent on the parameters related both to the size of the substituent and electronic properties of the molecule. An equation was obtained, statistically significant on the 99% level, which described about 71% of variance of activity data for the compounds under study as a function of molar refractivity of the substituent and the wave length at which absorption maximum occured.
Amides↗