The Experts below are selected from a list of 23133 Experts worldwide ranked by ideXlab platform
Wei Huang - One of the best experts on this subject based on the ideXlab platform.
-
caffeine protects against experimental acute pancreatitis by inhibition of inositol 1 4 5 trisphosphate receptor mediated ca2 release
Gut, 2017Co-Authors: Wei Huang, Matthew C Cane, Rajarshi Mukherjee, Peter Szatmary, Xiaoying ZhangAbstract:Objective Caffeine reduces toxic Ca 2+ signals in pancreatic acinar cells via inhibition of inositol 1,4,5-trisphosphate receptor (IP 3 R)-mediated signalling, but effects of other Xanthines have not been evaluated, nor effects of Xanthines on experimental acute pancreatitis (AP). We have determined effects of caffeine and its Xanthine metabolites on pancreatic acinar IP 3 R-mediated Ca 2+ signalling and experimental AP. Design Isolated pancreatic acinar cells were exposed to secretagogues, uncaged IP 3 or toxins that induce AP and effects of Xanthines, non-Xanthine phosphodiesterase (PDE) inhibitors and cyclic adenosine monophosphate and cyclic guanosine monophosphate (cAMP/cGMP) determined. The intracellular cytosolic calcium concentration ([Ca 2+ ] C ), mitochondrial depolarisation and necrosis were assessed by confocal microscopy. Effects of Xanthines were evaluated in caerulein-induced AP (CER-AP), taurolithocholic acid 3-sulfate-induced AP (TLCS-AP) or palmitoleic acid plus ethanol-induced AP (fatty acid ethyl ester AP (FAEE-AP)). Serum Xanthines were measured by liquid chromatography-mass spectrometry. Results Caffeine, dimethylXanthines and non-Xanthine PDE inhibitors blocked IP 3 -mediated Ca 2+ oscillations, while monomethylXanthines had little effect. Caffeine and dimethylXanthines inhibited uncaged IP 3 -induced Ca 2+ rises, toxin-induced Ca 2+ release, mitochondrial depolarisation and necrotic cell death pathway activation; cAMP/cGMP did not inhibit toxin-induced Ca 2+ rises. Caffeine significantly ameliorated CER-AP with most effect at 25 mg/kg (seven injections hourly); paraXanthine or theophylline did not. Caffeine at 25 mg/kg significantly ameliorated TLCS-AP and FAEE-AP. Mean total serum levels of dimethylXanthines and trimethylXanthines peaked at >2 mM with 25 mg/kg caffeine but at Conclusions Caffeine and its dimethylXanthine metabolites reduced pathological IP 3 R-mediated pancreatic acinar Ca 2+ signals but only caffeine ameliorated experimental AP. Caffeine is a suitable starting point for medicinal chemistry.
Xiaoying Zhang - One of the best experts on this subject based on the ideXlab platform.
-
caffeine protects against experimental acute pancreatitis by inhibition of inositol 1 4 5 trisphosphate receptor mediated ca2 release
Gut, 2017Co-Authors: Wei Huang, Matthew C Cane, Rajarshi Mukherjee, Peter Szatmary, Xiaoying ZhangAbstract:Objective Caffeine reduces toxic Ca 2+ signals in pancreatic acinar cells via inhibition of inositol 1,4,5-trisphosphate receptor (IP 3 R)-mediated signalling, but effects of other Xanthines have not been evaluated, nor effects of Xanthines on experimental acute pancreatitis (AP). We have determined effects of caffeine and its Xanthine metabolites on pancreatic acinar IP 3 R-mediated Ca 2+ signalling and experimental AP. Design Isolated pancreatic acinar cells were exposed to secretagogues, uncaged IP 3 or toxins that induce AP and effects of Xanthines, non-Xanthine phosphodiesterase (PDE) inhibitors and cyclic adenosine monophosphate and cyclic guanosine monophosphate (cAMP/cGMP) determined. The intracellular cytosolic calcium concentration ([Ca 2+ ] C ), mitochondrial depolarisation and necrosis were assessed by confocal microscopy. Effects of Xanthines were evaluated in caerulein-induced AP (CER-AP), taurolithocholic acid 3-sulfate-induced AP (TLCS-AP) or palmitoleic acid plus ethanol-induced AP (fatty acid ethyl ester AP (FAEE-AP)). Serum Xanthines were measured by liquid chromatography-mass spectrometry. Results Caffeine, dimethylXanthines and non-Xanthine PDE inhibitors blocked IP 3 -mediated Ca 2+ oscillations, while monomethylXanthines had little effect. Caffeine and dimethylXanthines inhibited uncaged IP 3 -induced Ca 2+ rises, toxin-induced Ca 2+ release, mitochondrial depolarisation and necrotic cell death pathway activation; cAMP/cGMP did not inhibit toxin-induced Ca 2+ rises. Caffeine significantly ameliorated CER-AP with most effect at 25 mg/kg (seven injections hourly); paraXanthine or theophylline did not. Caffeine at 25 mg/kg significantly ameliorated TLCS-AP and FAEE-AP. Mean total serum levels of dimethylXanthines and trimethylXanthines peaked at >2 mM with 25 mg/kg caffeine but at Conclusions Caffeine and its dimethylXanthine metabolites reduced pathological IP 3 R-mediated pancreatic acinar Ca 2+ signals but only caffeine ameliorated experimental AP. Caffeine is a suitable starting point for medicinal chemistry.
Christa E Muller - One of the best experts on this subject based on the ideXlab platform.
-
fast efficient and versatile synthesis of 6 amino 5 carboxamidouracils as precursors for 8 substituted Xanthines
Frontiers in Chemistry, 2019Co-Authors: Daniel Marx, Christa E Muller, Lukas M Wingen, Gregor Schnakenburg, Matthias ScholzAbstract:Substituted Xanthine derivatives are important bioactive molecules. Herein we report on a new, practical synthesis of 6-amino-5-carboxamidouracils, the main building blocks for the preparation of 8-substituted Xanthines, by condensation of 5,6-diaminouracil derivatives and various carboxylic acids using the recently developed non-hazardous coupling reagent COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate). Optimized reaction conditions led to the precipitation of pure products after only 5 to 10 min of reaction time. The method tolerates a variety of substituted 5,6-diaminouracil and carboxylic acid derivatives as starting compounds resulting in most cases in more than 80% isolated yield. Regioselectivity of the reaction yielding only the 5-carboxamido-, but not the 6-carboxamidouracil derivatives, was unambiguously confirmed by single X-ray crystallography and multidimensional NMR experiments. The described method represents a convenient, fast access to direct precursors of 8-substituted Xanthines under mild conditions without the necessity of hazardous coupling or chlorinating reagents.
-
Data_Sheet_2_Fast, Efficient, and Versatile Synthesis of 6-amino-5-carboxamidouracils as Precursors for 8-Substituted Xanthines.PDF
2019Co-Authors: Daniel Marx, Christa E Muller, Lukas M Wingen, Gregor Schnakenburg, Matthias S. ScholzAbstract:Substituted Xanthine derivatives are important bioactive molecules. Herein we report on a new, practical synthesis of 6-amino-5-carboxamidouracils, the main building blocks for the preparation of 8-substituted Xanthines, by condensation of 5,6-diaminouracil derivatives and various carboxylic acids using the recently developed non-hazardous coupling reagent COMU (1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate). Optimized reaction conditions led to the precipitation of pure products after only 5 to 10 min of reaction time. The method tolerates a variety of substituted 5,6-diaminouracil and carboxylic acid derivatives as starting compounds resulting in most cases in more than 80% isolated yield. Regioselectivity of the reaction yielding only the 5-carboxamido-, but not the 6-carboxamidouracil derivatives, was unambiguously confirmed by single X-ray crystallography and multidimensional NMR experiments. The described method represents a convenient, fast access to direct precursors of 8-substituted Xanthines under mild conditions without the necessity of hazardous coupling or chlorinating reagents.
-
fluorescent labeled selective adenosine a2b receptor antagonist enables competition binding assay by flow cytometry
Journal of Medicinal Chemistry, 2018Co-Authors: Meryem Kose, Sabrina Gollos, Tadeusz Karcz, Amelie Fiene, Fabian Heisig, Andrea Behrenswerth, Vigneshwaran Namasivayam, Katarzyna Kieckononowicz, Christa E MullerAbstract:Fluorescent ligands represent powerful tools for biological studies and are considered attractive alternatives to radioligands. In this study, we developed fluorescent antagonists for A2B adenosine receptors (A2BARs), which are targeted by antiasthmatic Xanthines and were proposed as novel targets in immuno-oncology. Our approach was to merge a small borondipyrromethene (BODIPY) derivative with the pharmacophore of 8-substituted Xanthine derivatives. On the basis of the design, synthesis, and evaluation of model compounds, several fluorescent ligands were synthesized. Compound 29 (PSB-12105), which displayed high affinity for human, rat, and mouse A2BARs (Ki = 0.2–2 nM) and high selectivity for this AR subtype, was selected for further studies. A homology model of the human A2BAR was generated, and docking studies were performed. Moreover, 29 allowed us to establish a homogeneous receptor–ligand binding assay using flow cytometry. These compounds constitute the first potent, selective fluorescent A2BAR li...
-
synthesis and preliminary evaluation of new 1 and 3 1 2 hydroxy 3 phenoxypropyl Xanthines from 2 amino 2 oxazolines as potential a1 and a2a adenosine receptor antagonists
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Stephane Massip, Christa E Muller, Jean Guillon, Daniela C G Bertarelli, Jeanjacques Bosc, Jeanmichel Leger, Svenja Lacher, Cecile Bontemps, Thibaut Dupont, Christian JarryAbstract:The development of potent and selective adenosine receptor ligands as potential drugs is an active area of research. Xanthines are one of the most important classes of adenosine receptor antagonists and have been widely developed in terms of affinity and selectivity for adenosine receptors. We recently developed new original pathways for the synthesis of Xanthine analogues starting from 5-substituted-2-amino-2-oxazoline 5 as a synthon. These procedures allowed us to selectively introduce a large, functionalized and β-adrenergic 2-hydroxy-3-phenoxypropyl pharmacophore at the 1- and 3-position of the Xanthine moiety which allowed further structural modifications. In this study, we present a new synthetic access to racemic Xanthine derivatives 1 – 4 from 5 , and their evaluation as adenosine A 1 , A 2A and A 3 receptor ligands in radioligand binding studies. The 2-hydroxy-3-phenoxypropyl moiety was well tolerated in the 3-position of the Xanthine core, while its introduction in the 1-position of the Xanthine moiety led to a large decrease in adenosine receptor affinity. 1,7-Dimethyl-3-[1-(2-chloro-3-phenoxypropyl)]-8-(3,4,5-trimethoxystyryl)Xanthine ( 2n ) was the most potent and selective A 2A antagonist of the present series ( K i = 44 nM, ≫200-fold selective vs A 1 ). 1-Propyl-3-[1-(2-hydroxy-3-phenoxypropyl)]-8-noradamantylXanthine ( 3f ) was identified as a potent ( K i A 1 = 21 nM) and highly selective (≫350-fold vs A 2A and A 3 receptor) adenosine A 1 receptor antagonist.
-
1,8-disubstituted Xanthine derivatives: synthesis of potent A2B-selective adenosine receptor antagonists.
Journal of medicinal chemistry, 2002Co-Authors: Alaa M. Hayallah, John W. Daly, Jesús Sandoval-ramírez, Ulrike Reith, Ulrike Schobert, Birgit Preiss, Britta Schumacher, Christa E MullerAbstract:3-Unsubstituted Xanthine derivatives bearing a cyclopentyl or a phenyl residue in the 8-position were synthesized and developed as A2B adenosine receptor antagonists. Compounds bearing polar substituents were prepared to obtain water-soluble derivatives. 1-Alkyl-8-phenylXanthine derivatives were found to exhibit high affinity for A2B adenosine receptors (ARs). 1,8-disubstituted Xanthine derivatives were equipotent to or more potent than 1,3,8-trisubstituted Xanthines at A2B ARs, but generally less potent at A1 and A2A, and much less potent at A3 ARs. Thus, the new compounds exhibited increased A2B selectivity versus all other AR subtypes. 9-DeazaXanthines (pyrrolo[2,3-d]pyrimidindiones) appeared to be less potent at A2B ARs than the corresponding Xanthine derivatives. 1-Propyl-8-p-sulfophenylXanthine (17) was the most selective compound of the present series, exhibiting a K(i) value of 53 nM at human A2B ARs and showing greater than 180-fold selectivity versus human A1 ARs. Compound 17 was also highly selective versus rat A1 ARs (41-fold) and versus the other human AR subtypes (A2A > 400-fold and A3 > 180-fold). The compound is highly water-soluble due to its sulfonate function. 1-Butyl-8-p-carboxyphenylXanthine (10), another polar analogue bearing a carboxylate function, exhibited a K(i) value of 24 nM for A2B ARs, 49-fold selectivity versus human and 20-fold selectivity versus rat A1 ARs, and greater than 150-fold selectivity versus human A2A and A3 ARs. 8-[4-(2-Hydroxyethylamino)-2-oxoethoxy)phenyl]-1-propylXanthine (29) and 1-butyl-8-[4-(4-benzyl)piperazino-2-oxoethoxy)phenyl]Xanthine (35) were among the most potent A2B antagonists showing K(i) values at A2B ARs of 1 nM, 57-fold (29) and 94-fold (35) selectivity versus human A1, ca. 30-fold selectivity versus rat A1, and greater than 400-fold selectivity versus human A2A and A3 ARs. The new potent, selective, water-soluble A2B antagonists may be useful research tools for investigating A2B receptor function.
Abdel Naser Zaid - One of the best experts on this subject based on the ideXlab platform.
-
Novel 1,3-Dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol-5-yl)Xanthines as Potent and Selective A2B Adenosine Receptor Antagonists
2016Co-Authors: Stefania Baraldi, Giulia Saponaro, Delia Preti, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-Xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-Xanthine 80 displaying very high affinity at A2BAR with good selectivity over AR subtypes (Ki = 4.0 nM, IC50 hA2B = 20 nM hA1/hA2B = 183, hA2A,hA3/hA2B > 250)
-
novel 1 3 dipropyl 8 3 benzimidazol 2 yl methoxy 1 methylpyrazol 5 yl Xanthines as potent and selective a2b adenosine receptor antagonists
Journal of Medicinal Chemistry, 2012Co-Authors: Stefania Baraldi, Giulia Saponaro, Delia Preti, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-Xanthine compounds with a simplified s...
Stefania Baraldi - One of the best experts on this subject based on the ideXlab platform.
-
Novel 1,3-Dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol-5-yl)Xanthines as Potent and Selective A2B Adenosine Receptor Antagonists
2016Co-Authors: Stefania Baraldi, Giulia Saponaro, Delia Preti, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-Xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-Xanthine 80 displaying very high affinity at A2BAR with good selectivity over AR subtypes (Ki = 4.0 nM, IC50 hA2B = 20 nM hA1/hA2B = 183, hA2A,hA3/hA2B > 250)
-
novel 1 3 dipropyl 8 3 benzimidazol 2 yl methoxy 1 methylpyrazol 5 yl Xanthines as potent and selective a2b adenosine receptor antagonists
Journal of Medicinal Chemistry, 2012Co-Authors: Stefania Baraldi, Giulia Saponaro, Delia Preti, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-Xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-Xanthine compounds with a simplified s...
