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Biomedical subjects

M Mahmoudian

Publications and source records attributed to M Mahmoudian.

At least 37 records · Page 2Linked to original sources
PubMed1999

Enzymic acylation of 506U78 (2-amino-9-beta-D-arabinofuranosyl-6- methoxy-9H-purine), a powerful new anti-leukaemic agent.

A practical enzymic approach for acylation of 506U78 (2-amino-9-beta-D-arabinofuranosyl-6-methoxy -9H-purine), a powerful anti-leukaemic agent, is described. Novozyme-435, an immobilized preparation of Candida antarctica lipase, was used to acylate 506U78 regioselectively at the 5'-position. This rendered the compound more soluble and bioavailable. Vinyl acetate was used as the acyl donor and reactions were carried out in anhydrous 1,4-dioxane with up to 100 g/l of substrate input. Bioconversions were optimised to achieve impurity (3'-mono- and di-acetates) levels of less than 0.5%.

Acylation↗
PubMed1998

Effect of diazoxide, an ATP-dependent potassium-channel opener, on isolated aortae of normal and diabetic rats.

1. The effect of diazoxide on the potassium-induced contraction and its inhibitory effect on noradrenaline-induced contraction were studied in the isolated aortic rings of normal and streptozocin-treated diabetic rats. 2. Diazoxide relaxed potassium-induced contraction in normal and diabetic rat aortae. There was no statistically significant difference in the relaxing effect of diazoxide in these two groups of rats. Glibenclamide inhibited the relaxing effect of diazoxide in normal and diabetic rat aortae to the same extent. Pretreatment of tissues with diazoxide prevented the noradrenaline-induced contraction. This inhibitory effect significantly differed between normal and diabetic rats. 3. It is concluded that, in the rat aorta, the state of potassium channels and the potency of diazoxide to open these channels are not affected by experimental diabetes. The observed differences between the responses of normal and diabetic aortae to the inhibitory effect of diazoxide on noradrenaline-induced contraction can be attributed to a mechanism(s) other than potassium-channel opening by diazoxide, which might be modified in diabetes, or to different consequences after potassium-channel opening in diabetic tissues compared with normal tissues.

Animals↗
PubMed1998

Effects of trypan blue on the action of adrenergic agonists in the guinea-pig isolated atrium.

It has been reported that trypan blue, a diazo dye with polyamphipathic structure, can inhibit the coupling of receptors to G-proteins. The present study was carried out to investigate the effect of trypan blue on the actions of adrenoceptor agonists in the guinea-pig atrium. Trypan blue (10 and 100 microM) antagonized the positive inotropic effects of isoprenaline and dobutamine by shifting their concentration-response curves to the right. With the selective beta 2-adrenoceptor agonist, salbutamol, there was a reduction of response in the presence of trypan blue. Therefore, we concluded that trypan blue diminish the response to beta-adrenoceptor agonists possibly via decoupling receptors from Gs. Trypan blue and similar agents, due to their unique mode of action, can be used as tools for the investigation of the mechanism of receptor-G protein coupling in the whole tissue preparation.

Adrenergic Agonists↗
PubMed1997

An efficient process for production of N-acetylneuraminic acid using N-acetylneuraminic acid aldolase.

N-acetyl-D-neuraminic acid (Neu5Ac) aldolase (EC 4.1.3.3) has bee reported for synthesis of Neu5Ac,1-5 but there are no reports of processes which do not have significant drawbacks for large-scale operation. Here, Neu5Ac aldolase from an overexpressing recombinant strain of Escherichia coli has been used to develop an immobilized enzyme process for production of Neu5Ac. The enzyme was immobilized onto Eupergit-C and could be reused many times in the reaction. Base-catalyzed epimerization of N-acetyl-D-glucosamine (GlcNAc) yielded GlcNAc/N-acetyl-D-mannosamine (ManNAc) mixtures (c 4:1) which could be used directly in the aldolase reaction; however, inhibition of the enzyme by GlcNAc limited the concentration of ManNAc which could be used in the reaction by this approach. This necessitated the addition of a large molar excess of pyruvate (five- to seven-fold) to drive the equilibrium over to Neu5Ac; nevertheless, a method has been developed to remove the excess pyruvate effectively by complexation with bisulfite, thus allowing Neu5Ac to be recovered by absorption onto an anion-exchange resin. In a second approach, a method has been developed to enrich GlcNAc/ManNAc mixtures for ManNAc. ManNAc can be used at high concentrations in the reaction, thus obviating the need to use a large molar excess of pyruvate. Neu5Ac can be isolated from such reaction mixtures by a simple crystallization. This work shows the importance of integrated process solutions for the effective scale-up of biotransformation reactions.

1-Propanol↗
PubMed1997

Determination of captopril in human serum by high performance liquid chromatography using solid-phase extraction.

A rapid, simple and sensitive assay was developed for determination of captopril in human serum. We employed silica gel cartridge for efficient extraction of captopril adduct from human serum. Captopril was trapped with p-bromophenacyl bromide (pBPB) to give captopril-pBPB adduct. A 4-ml benzene extract of 1 ml acidified serum was passed through 1 ml silica gel cartridge. Potential interfering compounds were removed with 4-ml benzene wash. The captopril-pBPB adduct was eluted with 0.5 ml acetonitrile. Of this acetonitrile solution (100 microliters) was injected on an ODS reverse phase HPLC column (chromatography conditions; mobile phase; acetonitrile-water-acetic acid (225:270:5, v/v/v), flow rate; 1 ml min-1, detection; UV at 263 nm). It is found that this method is accurate and does not require time consuming evaporation-concentration steps. Recovery exceeds 94% and analytical responses are linear over captopril concentration range from 50 up to 1000 ng ml-1. The coefficients of variation from 108 ng ml-1 to 605 ng ml-1 varied between 3.7-7.7% and the relative error did not exceed 3.7%. Therefore, this method can be used for routine clinical monitoring and in pharmacokinetic studies of captopril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

The cannabinoid receptor: computer-aided molecular modeling and docking of ligand.

A three-dimensional model of human cannabinoid receptor is constructed using computer-aided molecular modeling techniques. The helices of bacteriorhodopsin were used as the initial template to construct the transmembrane helices. The extracellular and intracellular loops were added using the SYBYL molecular modeling package. The extracellular N terminus was modeled on the basis of its similarity to rat oncomodulin. Similarly, the C terminus was constructed on the basis of similarity to bovine prothrombin fragment 1. The final structure was refined by several runs of minimization and dynamics calculation using the CHARMm package. delta 9-Tetra hydrocannabinol was docked into the internal cavity using the AUTODOCK program. Our study snows that there may be a calcium-binding site in the extracellular N terminus of this receptor. The ligand binds mainly to a hydrophobic site, which consists of residues Met-240, Trp-241 (TMH-4), Trp-356, Leu-359, Leu-360 (TMH-6), and Ala-283 (TMH-5). Its phenolic hydroxyl group forms a hydrogen bond with the carboxy group of Ala-198 (TMH-3). The results of modeling agree well with experimental QSAR studies.

Amino Acid Sequence↗
PubMed1997

Synthesis and biological activity of two new calcium-channel blockers, mebudipine and dibudipine.

Dihydropyridine derivative calcium-channel blockers are widely used in the therapy of hypertension, angina pectoris and other cardiovascular diseases. Because the prototype of dihydropyridine derivatives, nifedipine, does not have the optimum pharmacokinetic and pharmacodynamic characteristics, attempts have been made to synthesize other drugs in this class with improved properties. The synthesis and biological activity of two new calcium-channel blockers, non-symmetrical (mebudipine) and symmetrical (dibudipine) analogues of nifedipine, is described herein. The pharmacological potencies of the compounds were evaluated by studying their effects on the contractions of isolated guinea-pig ileum and rat aortic rings. Results were compared with those obtained from nifedipine. The new analogues and nifedipine inhibited the contractile response of guinea-pig ileum to electrical stimulation and the pIC50 value of the compounds did not differ significantly from each other. The compounds also antagonized the contractile responses of K+-depolarized guinea-pig ileum to cumulative concentrations of calcium. The inhibitory effect of mebudipine was significantly higher than that of nifedipine whereas the inhibitory effects of dibudipine and nifedipine were not different. All three compounds relaxed KCl (40 mM)-treated isolated aortic rings; the pIC50 values for relaxation were: mebudipine > nifedipine > dibudipine. It is concluded that these new dihydropyridine derivatives are potent relaxants of vascular and ileal smooth muscles and therefore have high potential for use as antihypertensive and anti-anginal agents.

Animals↗
PubMed1996

Diabetes-induced changes in the contractility of the aorta and pA2 of nifedipine in the rat.

Diabetes-induced changes in the calcium influx and contractile responses of aortic rings to various drugs were investigated in streptozotocin-treated rats. Diabetes is associated with calcium influx into the aortic rings (1.5-and 2.5-fold, respectively, after either KCl or noradrenaline stimulation compared with normal). The maximum KCl-induced contraction of the arorta in diabetic rats was reduced by 38%, but the EC50 of KCl remained unchanged. The pA2 of nifedipine for inhibiting the contractile response of aorta to KCl decreased one order of magnitude in the diabetic rats (8.26 vs 9.03 for non-diabetic rats). It is concluded that diabetes reduces the sensitivity of aortic tissue to nifedipine and may affect the stimulation-contraction coupling of vascular smooth muscle in such a way that a higher influx of calcium results after stimulation and that this may be responsible for diabetes-induced vascular complications.

Animals↗
PubMed1996

Computer-aided molecular modeling of cathepsin E, a possible endothelin-converting enzyme.

A three-dimensional model of human cathepsin E, a possible endothelin-converting enzyme, is constructed using computer-aided molecular modeling techniques. The structure of porcine pepsin, another aspartic protease, was used as a template. The final structure, after all gaps and deletions were made, was optimized using the AMBER-4 package. A dipeptide (Trp-Val) representing the substrate was docked in the putative active site and the whole structure was optimized after several runs of minimization and dynamics calculations. The result of this modeling study showed that the structure of cathepsin E is similar to that of porcine pepsin and has three disulfide bonds that are conserved in both enzymes. There are two Asp-Thr-Gly sequences at the active site of enzyme. The active site cavity is large enough to accommodate its substrate.

Amino Acid Sequence↗
PubMed1996

Effect of trypan blue on the action of acetylcholine, histamine and salbutamol in the isolated guinea-pig ileum.

It has been reported that trypan blue, a diazo dye with polyamphipatic structure, can inhibit the coupling of receptors to G-proteins. This inhibition of G-protein coupling has been investigated in isolated guinea-pig ileum. It was found that trypan blue could elicit a slight but dose-dependent contractile response in isolated guinea-pig ileum (4.5% of maximum contractile response induced by acetylcholine). While trypan blue potentiated the effect of histamine and shifted its dose-response curve to the left, it did not affect the contractile effects of acetylcholine. Furthermore, the relaxation which has been induced by salbutamol, a beta 2 agonist, was inhibited by trypan blue. It is concluded that trypan blue, as shown in biochemical studies, act selectively and can uncouple Gs-protein from beta 1 receptors. However, the effect of trypan blue on the whole tissue preparation depends on the type of G-protein involved and post G-protein processes which are stimulated after receptor activation. Trypan blue and similar agents could provide useful tools for further investigations of the mechanism of receptor-G protein coupling in the whole tissue preparation.

Acetylcholine↗
PubMed1994

The complex of human Gs protein with the beta 3 adrenergic receptor: a computer-aided molecular modeling study.

Three-dimensional (3D) models of the human Gs protein, the human beta 3 adrenergic receptor and their complex are constructed using computer-aided molecular modeling techniques. The structures of bacterial EF-tu 200 and bacteriorhodopsin were used as starting points for modeling the Gs protein and beta 3 receptor, respectively. Experimental data are used as constraints to guide the modeling. The resulting 3D structures of the Gs protein, the beta 3 receptor and their complex are in accord with the experimental data. It is found that the third intracellular loop of the beta 3 receptor as well as its C-terminus are involved in the binding. Various residues of N-terminus and C-terminus of the Gs protein also participate in the binding. The model of the complex suggests that the Gs protein binds to the beta 3 receptor in such a way that it will be placed in the interface of membrane and intracellular space. This orientation is supported by experimental data. It is concluded that the modeled structure of the complex of the alpha subunit of the human Gs protein and the beta 3 adrenergic receptor is in agreement with the experimental data and it can provide a basis for understanding the way these proteins interact.

Amino Acid Sequence↗
PubMed1993

Enzymatic production of optically pure (2'R-cis)-2'-deoxy-3'-thiacytidine (3TC, lamivudine): a potent anti-HIV agent.

Although equipotent in terms of antiviral activity, the two enantiomers of 2'-deoxy-3'-thiacytidine (BCH 189) differ markedly in their cytotoxicity. (2'R-cis)-2'-deoxy-3'-thiacytidine (3TC) is substantially less toxic than its optical antipode, and is undergoing development for the therapy of HIV infection. Cytidine deaminase from Escherichia coli is shown here to deaminate 2'-deoxy-3'-thiacytidine enantioselectively to leave 3TC essentially optically pure. This reaction has been used to develop a process for production of 3TC in multikilogram amounts. The production of cytidine deaminase was enhanced by strain improvement, fermentation development, and finally by cloning and overexpression of the gene. The enzyme was immobilized on Eupergit-C, which allowed it to be reused many times. The biotransformation conditions were optimized so that the best use could be made of the catalyst. A robust scaleable product isolation process was developed to yield the crystalline product. Overall, yields through the resolution process of 76% were obtained. All aspects of this process are capable of substantial further scaleup with only minor modifications.

Antiviral Agents↗
PubMed1992

The mechanism of action and mode of inhibition of dihydroorotate dehydrogenase. A quantum chemical study.

Semiemperical quantum chemical calculations have been applied to study the reaction mechanism and mode of inhibition of dihydroorotate dehydrogenase. The structure of substrate, intermediate, product and various inhibitors of dihydroorotate dehydrogenase were optimized using MNDO method and the geometry, heat of formation and the net atomic partial charges of optimized molecules, as well as the energy of the reaction path were calculated. This study shows that the carbanion intermediate of this reaction is rather stable (heat of formation = -134.5 kcal) and readily forms upon nucleophilic attack by groups such as hydroxyl ion. There is good correlation between electronic properties and the biological activities of various inhibitors of this enzyme and the geometry of the most active inhibitor resembles closely that of the intermediate of the reaction. Therefore, it is concluded that the enzymatic oxidation of dihydroorotate dehydrogenase proceeds via formation of an intermediate and the inhibitors bind to the active site of this enzyme in the place of this intermediate.

Binding Sites↗
PubMed1992

Stereoselective epoxidation of phenyl allyl ether by alkene-utilizing bacteria.

Eighteen newly isolated ethene- and propene-utilizing bacteria were screened for the ability to produce phenyl glycidyl ether, a common precursor for the synthesis of beta blockers, from phenyl allyl ether. These organisms included Aerococcus, Alcaligenes, Micrococcus and Staphylococcus spp. and a variety of Gram-negative, Gram-positive and Gram-variable mesophilic rods/coccobacilli not yet identified. The majority of ethene- and propene-grown cultures (14 strains) accumulated phenyl glycidyl ether (0.4-1.7 mM) as the sole oxidation product. The bioconversions with the three most promising ethene-utilizers (M26, M90C, M93A) were scaled-up to yield essentially optically pure (enantiomeric excess = 93%) S-(+)-phenyl glycidyl ether. This is currently under investigation for commercial production of optically pure beta blockers.

Alkenes↗
PubMed1992

Resolution of 4-amino-cyclopentanecarboxylic acid methyl esters using hydrolytic enzymes.

A number of esterases (EC 3.1.1.1) and lipases (EC 3.1.1.3) of microbial and mammalian origin were screened for the ability to resolve racemic 4-amino-cyclopentanecarboxylic acid methyl ester derivatives as potential intermediates in the production of carbocyclic nucleosides. Surprisingly, functionalization of the remote amino group had a profound effect on both the rate and enantioselectivity of hydrolysis of the methyl ester. 4-(Benzoylamino)-2-cyclopentenecarboxylic acid, methyl ester (V) with pig liver esterase gave the highest enantioselectivity. The residual ester, which was of the correct absolute stereochemistry [(+) 1S, 4R] for carbocyclic nucleoside synthesis, could be obtained in high optical purity. Optimization of pH, solvent type, and concentration improved the enantioselectivity of the process by a further twofold.

Animals↗
PubMed1991

Quantitative structure-activity relationships (QSARs) of pyrimidine nucleosides as HIV-1 antiviral agents.

The structural requirements for the antiviral activity of pyrimidine nucleosides against HIV-1 virus was evaluated with the Hansch SAR analysis. Antiviral activity is best related to the hydrophobicity and steric (L and B3) properties of the substituent at the C5 of pyrimidine ring. Further, the antiviral activity is related to B4 of the substituent at position 3' of the sugar ring with a positive slope. The activity of both uracil and cytosine derivatives can be related to their structure by the same equations, which indicates that the SARs are similar in these two groups of congeners. These results suggest that compounds with a small substituent at the 5 position of the pyrimidine ring and a flat substituent at the 3' position of the sugar ring will be the most active compounds against HIV-1 virus.

Antiviral Agents↗
PubMed1990

The bioavailability of griseofulvin from microsized and ultramicrosized tablets in nonfasting volunteers.

Tablets of either microsized or ultramicrosized griseofulvin (2 x 125 mg), were administered to 6 healthy volunteers of either sex just before a breakfast containing 4o g. of butter. The plasma concentration of griseofulvin were determined 1, 3, 5, 7, 9, 24, and 32 h. after dosing using a spectrofluorometric method, and pharmacokinetic parameters (Cp max, t max, AUC 0 - greater than 32) were calculated. These parameters were found to be; Cp max = 0.0.681 +/- 0.1 mu/ml, t max. = 2.51 +/- 0.33 h. and AUC = 14.14 +/- 2.33 micrograms h/ml for microsized tablets and Cp max = 0.80 +/- 0.08 +/- g/ml, t max = 2.44 +/- 0.54 and AUC = 16.25 +/- 1.16 microgram h/ml for ultramicrosized tablets. Our results show that mean peak plasma level and AUC (0 - greater than 32) are only slightly higher for the ultramicrosized preparation and the time to peak plasma level is similar in two preparations. Therefore, it is concluded that coadministration of griseofulvin with food will tend to reduce the difference between the bioavailability of the two type of preparations.

Adult↗