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Arpád Márki

Publications and source records attributed to Arpád Márki.

11 recordsLinked to original sources
PubMed2006

Receptor-based QSAR studies of non-peptide human oxytocin receptor antagonists.

In the present study, QSAR calculations were performed on the receptor-based alignment of 58 non-peptide human oxytocin receptor antagonists. With the aid of different scoring functions (AutoDock 3.05 built-in and X-Score 1.2) the evolved receptor-ligand complexes were characterized. By means of various datasets it was confirmed that the scoring functions were not capable to predict the biological activity correctly in compounds containing a rigid derivative in the variable region. To improve the pKi prediction 3D-QSAR calculation was performed. The regions related to the biological activity were determined by using cross-validated r2(q2)-guided region selection (q2-GRS) method. The predictive power of the CoMFA model [r(pred)2=0.89, q2(LMO, five groups)=0.695+/-0.034] allowed prediction of the biological activities of newly synthesized compounds and confirmed the receptor-based alignment.

Benzoxazines↗
PubMed2006

Possible dynamic anchor points in a benzoxazinone derivative-human oxytocin receptor system--a molecular docking and dynamics calculation.

In this study, we performed a molecular docking and dynamics simulation for a benzoxazinone-human oxytocin receptor system to determine the possible hydrophobic and electrostatic interaction points in the dynamic complex. After the homology modeling, the ligand was docked into the putative active using AutoDock 3.05. After the application of energetic and structural filters, the complexes obtained were further refined with a simulated annealing protocol (AMBER8) to remove steric clashes. Three complexes were selected for subjection to the molecular dynamics simulation (5 ns), and the results on the occurrence of average anchor points showed a stable complex between the benzoxazinone derivative and the receptor. The complex could be used as a good starting point for further analysis with site-directed mutagenesis, or further computational research.

Animals↗
PubMed2006

Comparative study of eight oxytocin antagonists by simulated annealing.

In this study, eight oxytocin (OT) antagonists were subjected to conformational analysis. By means of simulated annealing, 2,000 structures were generated to sample the conformational space. The preferred main-chain and side-chain dihedral angles, intramolecular H-bond interactions (types 1<--4 and 1<--3), and secondary-structure elements (beta-turns) were determined in the series of compounds. The influence of the modified amino acid on these structural elements was established; the values determined will be used as filtration criterion in preliminary research.

Hydrogen Bonding↗
PubMed2005

Neighboring group participation. Part 16. Stereoselective synthesis and receptor-binding examination of the four stereoisomers of 16-bromomethyl-3,17-estradiols.

The four possible isomers of 3-benzyloxy-16-hydroxymethylestra-1,3,5(10)-trien-17-ol (1a-4a) with proven configurations were converted into the corresponding 3-benzyloxy-16-bromomethylestra-1,3,5(10)-triene-3,17-diols (5e-8e). Depending on the reaction conditions the cis isomers of 3-benzyloxy-16-hydroxymethylestra-1,3,5(10)-trien-17-ol (1a and 2a) were transformed into 3-benzyloxy-16-bromomethylestra-1,3,5(10)-trien-17-yl acetate (5b and 6b) or 16-bromomethyl-3-hydroxyestra-1,3,5(10)-trien-17-yl acetate (5c and 6c) on treatment with HBr and acetic acid. The mechanism of the process can be interpreted as involving front-side neighboring group participation. Under similar experimental conditions, the trans isomers (3a and 4a) yielded only 3-benzyloxy-16-acetoxymethylestra-1,3,5(10)-trien-17-yl acetates (3b and 4b) or 16-acetoxymethylestra-1,3,5(10)-triene-3,17-diyl diacetates (3d and 4d). Both the cis (1a and 2a) and the trans (3a, and 4a) isomers were transformed into 16-bromomethylestra-1,3,5(10)-trien-17-ol (5a-8a) by the Appel reaction on treatment with CBr4/Ph3P. Debenzylation of 5a-8a was carried out with HBr and acetic acid to yield 5e-8e. The debenzylation process in the presence of acetic anhydride produces the diacetates 5d-8d. The structures of the compounds were determined by means of MS, 1H NMR and 13C NMR spectroscopic methods. Compounds 5c-8c and 5e-8e were tested in a radioligand-binding assay. Except for the affinity of 7e for the estrogen receptor (Ki=2.55 nM), the affinities of the eight compounds (5c-8c and 5e-8e) for the estrogen, androgen and progesterone receptors are low (Ki > 0.55, 0.52 and 0.21 microM, respectively).

Animals↗
PubMed2005

The 3D structure of the binding pocket of the human oxytocin receptor for benzoxazine antagonists, determined by molecular docking, scoring functions and 3D-QSAR methods.

Molecular docking and 3D-QSAR studies were performed to determine the binding mode for a series of benzoxazine oxytocin antagonists taken from the literature. Structural hypotheses were generated by docking the most active molecule to the rigid receptor by means of AutoDock 3.05. The cluster analysis yielded seven possible binding conformations. These structures were refined by using constrained simulated annealing, and the further ligands were aligned in the refined receptor by molecular docking. A good correlation was found between the estimated deltaG(bind) and the pKi values for complex F. The Connolly-surface analysis, CoMFA and CoMSIA models q2(CoMFA) = 0.653, q2(CoMSA) = 0.630 and r2(pred,CoMFA) = 0.852 , r2(pred,CoMSIA) = 0.815) confirmed the scoring function results. The structural features of the receptor-ligand complex and the CoMFA and CoMSIA fields are in closely connected. These results suggest that receptor-ligand complex F is the most likely binding hypothesis for the studied benzoxazine analogs.

Benzoxazines↗
PubMed2005

Pregnancy-induced decrease in the relaxant effect of terbutaline in the late-pregnant rat myometrium: role of G-protein activation and progesterone.

The effectiveness of beta2-agonists in preterm delivery is reduced by several factors. The aim of this study was to determine the influence of late pregnancy in the uterus-relaxing effect of terbutaline in the rat in vitro. Rat uterine tissues from late pregnancy (days 15, 18, 20 and 22) were used. In vitro electrical field-stimulation (EFS) was used to evoke contractions. The radioligand-binding technique, reverse transcription-polymerase chain reaction and radioimmunoassay technique were used to determine the beta-adrenergic receptor density and mRNA level and the plasma sex hormone level, respectively. The activated G-protein level of the beta-adrenergic receptors was investigated by a radiolabelled GTP binding assay.EFS-induced contractions were inhibited by terbutaline. This effect decreased towards term with respect to both the EC50 and maximal inhibition values. A drop in plasma progesterone level was also detected. Binding studies revealed an increase in beta-adrenergic receptor number on the last day of pregnancy, which correlated with the change in receptor mRNA level. The G-protein-activating effect of terbutaline decreased continuously between days 15 and 20. Surprisingly, terbutaline decreased the G-protein activation to below the basal level on day 22. However, progesterone pretreatment set back the uterine action of terbutaline, increased the density of the beta2-adrenergic receptors and their mRNA level and increased the G-protein-activating property of terbutaline. These data provide evidence of a pregnancy-induced decrease in activated G-protein level after beta2-agonist stimulation. The decrease in plasma progesterone level has a crucial role in this process. The effects of beta2-adrenergic receptor agonists in tocolytic therapy may possibly be potentiated with progesterone.

Animals↗
PubMed2004

Investigation of estrogen receptor alpha and beta mRNA expression in the pregnant rat uterus.

Although the expressions of the estrogen receptor (ER) subtypes have been demonstrated in a large number of estrogen target tissues, to date no evidence has been reported as to how the expressions of the alpha (alpha) and beta (beta) ER subtype mRNA alter in the rat uterus during pregnancy. The aims of the present study were to obtain information concerning the changes in the ER and the progesterone receptor (PR) in early pregnancy and to determine the alterations in the ER subtype mRNA in the pregnant rat uterus. To demonstrate the ER and PR densities, radioligand saturation assay was used. The reverse-transcription-polymerase chain reaction (RT-PCR) was applied to characterize the alterations in the ER subtype mRNA. ER expression was highest on day 5 of pregnancy (Bmax = 637.40 +/- 76.10 fmol/mg). The PR expression did not change significantly until day 8, but the protein density was increased on day 8 of pregnancy. The ERalpha mRNA expression was active during pregnancy, maximum expression was attained on day 5; a gradual decrease was then observed until the second half of pregnancy when its expression continuously increased up to the day of labor (day 22). Since the attachment of the blastocyst, an event that is dependent on estradiol in the progesterone-primed uterus of the rat, occurs on day 5 of pregnancy and the levels of the ER protein and the ERalpha mRNA on day 5 of pregnancy was the highest, it could be supposed that this subtype of ER might regulate implantation. The ERbeta mRNA was detected only from day 7 to day 15, with a maximum level on day 8. The expression of this ER subtype might be related to the development of decidual tissue.

Animals↗
PubMed2003

Alpha-adrenergic blockade: a possible mechanism of tocolytic action of certain benzodiazepines in a postpartum rat model in vivo.

Benzodiazepines are frequently used for the treatment of maternal psychiatric disorders during pregnancy. Besides their anxiolytic effect, they are reported to exert a direct relaxing action on several smooth muscle preparations, including the uterus. In the present study, the possibility of the involvement of alpha(1)-adrenergic receptors in this peripheral effect is investigated. The tocolytic potencies of diazepam, midazolam and nitrazepam are assessed in vivo in a postpartum rat model, together with other drugs known to bind to alpha-adrenoceptors (e.g. alpha(1)-antagonists, tricyclic compounds and droperidol). The interactions of some benzodiazepines and norepinephrine were also examined in an isolated in vitro system. The affinities of these agents for the receptor in question were additionally tested by radioligand displacement assay. A correlation was found between the tocolytic potencies and inhibition constants of the tested drugs, suggesting that the smooth muscle-relaxing effect of these benzodiazepines is mediated through modulation of the alpha(1)-adrenergic receptors.

Adrenergic alpha-Antagonists↗
PubMed2003

Synthesis and receptor-binding examinations of the normal and 13-epi-D-homoestrones and their 3-methyl ethers.

An effective epimerization of the normal estrone 3-methyl and 3-benzyl ethers by using o-phenylenediamine and AcOH made the possibility for facile entry into the 13alpha-estrone series. Combination of this synthetic methodology with an isolation step carried out by means of the Girard-P reagent, the corresponding ethers of 13-epi-estrone were obtained in excellent yields. The 3-hydroxy and 3-methoxy D-homoestrone derivatives in both the normal and the 13alpha-estrone series were then synthesized and tested in vitro in a radioligand-binding assay. The estrogen receptor recognizes these compounds, but their relative binding affinities (RBAs) are lower than that of the reference compound 3,17beta-estradiol. The progesterone receptor-binding affinities of the four D-homo derivatives were also tested showing low values for 13alpha-D-homoestrone and its 3-methyl ether. Pharmacologically, these 13alpha-D-homoestrone derivatives are estrogen receptor-selective molecules.

Binding Sites↗
PubMed2002

Synthesis and receptor-binding examination of 16-hydroxymethyl-3,17-estradiol stereoisomers.

The four 16-hydroxymethylestra-1,3,5(10)-triene-3,17-diol isomers were synthesized and tested in a radioligand-binding assay. The estrogen receptor recognizes these compounds, but their relative binding affinities are lower than 2.0% relative to that of the reference molecule estra-1,3,5(10)-triene-3,17beta-diol. The affinities of the tested compounds for the androgen and progesterone receptors are very low (K(i)> 100 microm and 1 microM, respectively). The prepared 16-hydroxymethylestra-1,3,5(10)-triene-3,17-diol isomers are therefore estrogen receptor-selective molecules.

Animals↗
PubMed2002

Synthesis and receptor-binding examination of 16-hydroxymethyl-3,17-estradiol stereoisomers.

The four 16-hydroxymethylestra-1,3,5(10)-triene-3,17-diol isomers were synthesized and tested in a radioligand-binding assay. The estrogen receptor recognizes these compounds, but their relative binding affinities are lower than 2.0% relative to that of the reference molecule estra-1,3,5(10)-triene-3,17beta-diol. The affinities of the tested compounds for the androgen and progesterone receptors are very low (K(i)> 100 microm and 1 microM, respectively). The prepared 16-hydroxymethylestra-1,3,5(10)-triene-3,17-diol isomers are therefore estrogen receptor-selective molecules.

Animals↗