Tag: M.W=500-550

Roseti, Cristina published the artcileAdenosine receptor antagonists alter the stability of human epileptic GABA_A receptors, COA of Formula: C27H29N5O5, the publication is Proceedings of the National Academy of Sciences of the United States of America (2008), 105(39), 15118-15123, database is CAplus and MEDLINE.

We examined how the endogenous anticonvulsant adenosine might influence γ-aminobutyric acid type A (GABA_A) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 μM), GABA_A receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABA_A-current (I_GABA) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/mL), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced I_GABA run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated IGABA run-down in ≈40% and ≈20% of tested oocytes, resp. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 μM) potentiated I_GABA run-down but only in ≈20% of tested oocytes. CGS15943 administration again decreased I_GABA run-down in patch-clamped neurons from either human or rat neocortex slices. I_GABA run-down in pyramidal neurons was equivalent in A1 receptor-deficient and wt neurons but much larger in neurons from A2A receptor-deficient mice, indicating that, in mouse cortex, GABA_A-receptor stability is tonically influenced by A2A but not by A1 receptors. I_GABA run-down from wt mice was not affected by 2-CA, suggesting maximal ARs activity by endogenous adenosine. Our findings strongly suggest that cortical A2-A3 receptors alter the stability of GABA_A receptors, which could offer therapeutic opportunities.

Proceedings of the National Academy of Sciences of the United States of America published new progress about 264622-53-9. 264622-53-9 belongs to amides-buliding-blocks, auxiliary class GPCR/G Protein,Adenosine Receptor, name is N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide, and the molecular formula is C27H29N5O5, COA of Formula: C27H29N5O5.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Zheng, Deqiang published the artcileSynthesis of regorafenib, Synthetic Route of 1019206-88-2, the publication is Zhongguo Yiyao Gongye Zazhi (2016), 47(5), 528-530, database is CAplus.

Regorafenib was synthesized from 3-fluoro-4-nitrophenol (2) via reduction nitro group, nucleophilic substitution with N-methyl-4-chloropyridine-2-carboxamide (5), condensation with 4-chloro-3-(trifluoromethyl) Ph isocyanate (8), and then recrystallization by salt formation and neutralization with an overall yield of 63.8% (based on 2).

Zhongguo Yiyao Gongye Zazhi published new progress about 1019206-88-2. 1019206-88-2 belongs to amides-buliding-blocks, auxiliary class Protein Tyrosine Kinase/RTK,VEGFR, name is 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide hydrate, and the molecular formula is C15H14O3, Synthetic Route of 1019206-88-2.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Li, Qilan published the artcileZM241385, DPCPX, MRS1706 are inverse agonists with different relative intrinsic efficacies on constitutively active mutants of the human adenosine A_2B receptor, Recommanded Product: N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide, the publication is Journal of Pharmacology and Experimental Therapeutics (2007), 320(2), 637-645, database is CAplus and MEDLINE.

The human adenosine A_2B receptor belongs to class A G protein-coupled receptors (GPCRs). In our previous work, constitutively active mutant (CAM) human adenosine A_2B receptors were identified from a random mutation bank. In the current study, three known A_2B receptor antagonists, 4-{2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl-amino]ethyl}phenol (ZM241385), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS1706) were tested on wild-type and nine CAM A_2B receptors with different levels of constitutive activity in a yeast growth assay. All three compounds turned out to be inverse agonists for the adenosine A_2B receptor because they were able to fully reverse the basal activity of four low-level constitutively active A_2B receptor mutants and to partially reverse the basal activity of three medium-level constitutively active A_2B receptor mutants. We also discovered two highly constitutively active mutants whose basal activity could not be reversed by any of the three compounds A two-state receptor model was used to explain the exptl. observations; fitting these yielded the following relative intrinsic efficacies for the three inverse agonists ZM241385, DPCPX, and MRS1706: 0.14±0.03, 0.35±0.03, and 0.31±0.02, resp. Moreover, varying L, the ratio of active vs. inactive receptors in this model, from 0.11 for mutant F84L to 999 for two highly constitutively active mutants yielded simulated dose-response curves that mimicked the exptl. curves. This study is the first description of inverse agonists for the human adenosine A_2B receptor. Moreover, the use of receptor mutants with varying levels of constitutive activity enabled us to determine the relative intrinsic efficacy of these inverse agonists.

Journal of Pharmacology and Experimental Therapeutics published new progress about 264622-53-9. 264622-53-9 belongs to amides-buliding-blocks, auxiliary class GPCR/G Protein,Adenosine Receptor, name is N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide, and the molecular formula is C27H29N5O5, Recommanded Product: N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Cheng, Feixiong published the artcileInsights into binding modes of adenosine A_2B antagonists with ligand-based and receptor-based methods, Computed Properties of 264622-53-9, the publication is European Journal of Medicinal Chemistry (2010), 45(8), 3459-3471, database is CAplus and MEDLINE.

Ligand-based and receptor-based methods were used to investigate the binding modes of human adenosine A_2B antagonists. At first, pharmacophore models were developed based on 140 diverse A_2B antagonists from literature. Meanwhile, the structural model of A_2B receptor was built up based on the crystal structure of human A_2A receptor and validated by Induced Fit docking, Glide-XP and Glide-SP docking. Two models matched each other very well and some important implications were hence obtained. The residues of Phe173 and Glu174 in the second extracellular loop and Asn254 were crucial to the antagonists binding to form π-π stacking and hydrogen-bonding interactions. These findings would be very helpful for the discovery of novel and potent A_2B antagonists.

European Journal of Medicinal Chemistry published new progress about 264622-53-9. 264622-53-9 belongs to amides-buliding-blocks, auxiliary class GPCR/G Protein,Adenosine Receptor, name is N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide, and the molecular formula is C27H29N5O5, Computed Properties of 264622-53-9.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Mueller, Martin published the artcileImpact of co-administered stabilizers on the biopharmaceutical performance of regorafenib amorphous solid dispersions, Quality Control of 1019206-88-2, the publication is European Journal of Pharmaceutics and Biopharmaceutics (2021), 189-199, database is CAplus and MEDLINE.

Poor solubility of drug candidates is a well-known and thoroughly studied challenge in the development of oral dosage forms. One important approach to tackle this challenge is the formulation as an amorphous solid dispersion (ASD). To reach the desired biopharmaceutical improvement a high supersaturation has to be reached quickly and then be conserved long enough for absorption to take place. In the presented study, various formulations of regorafenib have been produced and characterized in biorelevant in-vitro experiments Povidone-based formulations, which are equivalent to the marketed product Stivarga, showed a fast drug release but limited stability and robustness after that. In contrast, HPMCAS-based formulations exhibited excellent stability of the supersaturated solution, but unacceptably slow drug release. The attempt to combine the desired attributes of both formulations by producing a ternary ASD failed. Only co-administration of HPMCAS as an external stabilizer to the rapidly releasing Povidone-based ASDs led to the desired dissolution profile and high robustness. This optimized formulation was tested in a pharmacokinetic animal model using Wistar rats. Despite the promising in-vitro results, the new formulation did not perform better in the animal model. No differences in AUC could be detected when compared to the conventional (marketed) formulation. These data represent to first in-vivo study of the new concept of external stabilization of ASDs. Subsequent in-vitro studies revealed that temporary exposure of the ASD to gastric medium had a significant and long-lasting effect on the dissolution performance and externally administered stabilizer could not prevent this sufficiently. By applying the co-administered HPMCAS as an enteric coating onto Stivarga tablets, a new bi-functional approach was realized. This approach achieved the desired tailoring of the dissolution profile and high robustness against gastric medium as well as against seeding.

European Journal of Pharmaceutics and Biopharmaceutics published new progress about 1019206-88-2. 1019206-88-2 belongs to amides-buliding-blocks, auxiliary class Protein Tyrosine Kinase/RTK,VEGFR, name is 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide hydrate, and the molecular formula is C21H17ClF4N4O4, Quality Control of 1019206-88-2.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Wei, Jing published the artcile3D-Pharmacophore Models for Selective A_2A and A_2B Adenosine Receptor Antagonists, Product Details of C27H29N5O5, the publication is Journal of Chemical Information and Modeling (2007), 47(2), 613-625, database is CAplus and MEDLINE.

Three-dimensional pharmacophore models were generated for A_2A and A_2B adenosine receptors (ARs) based on highly selective A_2A and A_2B antagonists using the Catalyst program. The best pharmacophore model for selective A_2A antagonists (Hypo-A_2A) was obtained through a careful validation process. Four features contained in Hypo-A_2A (one ring aromatic feature (R), one pos. ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A_2A AR selectivity. The best pharmacophore model for selective A_2B antagonists (Hypo-A_2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A_2B antagonists training set. Hypo-A_2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A_2B AR binding affinity and are essential for A_2B selectivity. Both A_2A and A_2B pharmacophore models have been validated toward a wide set of test mols. containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biol. activities and designing novel selective adenosine receptor ligands.

Journal of Chemical Information and Modeling published new progress about 264622-53-9. 264622-53-9 belongs to amides-buliding-blocks, auxiliary class GPCR/G Protein,Adenosine Receptor, name is N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide, and the molecular formula is C12H9N3O4, Product Details of C27H29N5O5.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Tanaka, Masayoshi published the artcileAdenosine A_2B receptor down-regulates metabotropic glutamate receptor 5 in astrocytes during postnatal development, HPLC of Formula: 264622-53-9, the publication is Glia (2021), 69(11), 2546-2558, database is CAplus and MEDLINE.

Metabotropic glutamate receptor 5 (mGluR5) in astrocytes is a key mol. for controlling synapse remodeling. Although mGluR5 is abundant in neonatal astrocytes, its level is gradually down-regulated during development and is almost absent in the adult. However, in several pathol. conditions, mGluR5 re-emerges in adult astrocytes and contributes to disease pathogenesis by forming uncontrolled synapses. Thus, controlling mGluR5 expression in astrocyte is critical for several diseases, but the mechanism that regulates mGluR5 expression remains unknown. Here, we show that ATP (ATP)/adenosine-mediated signals down-regulate mGluR5 in astrocytes. First, in situ Ca2+ imaging of astrocytes in acute cerebral slices from post-natal day (P)7-P28 mice showed that Ca2+ responses evoked by (S)-3,5-dihydroxyphenylglycine (DHPG), a mGluR5 agonist, decreased during development, whereas those evoked by ATP or its metabolite, adenosine, increased. Second, ATP and adenosine suppressed expression of the mGluR5 gene, Grm5, in cultured astrocytes. Third, the decrease in the DHPG-evoked Ca2+ responses was associated with down-regulation of Grm5. Interestingly, among several adenosine (P1) receptor and ATP (P2) receptor genes, only the adenosine A2B receptor gene, Adora2b, was up-regulated in the course of development. Indeed, we observed that down-regulation of Grm5 was suppressed in Adora2b knockout astrocytes at P14 and in situ Ca2+ imaging from Adora2b knockout mice indicated that the A2B receptor inhibits mGluR5 expression in astrocytes. Furthermore, deletion of A2B receptor increased the number of excitatory synapse in developmental stage. Taken together, the A2B receptor is critical for down-regulation of mGluR5 in astrocytes, which would contribute to terminate excess synaptogenesis during development.

Glia published new progress about 264622-53-9. 264622-53-9 belongs to amides-buliding-blocks, auxiliary class GPCR/G Protein,Adenosine Receptor, name is N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide, and the molecular formula is C14H31NO2, HPLC of Formula: 264622-53-9.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Sherbiny, Farag F. published the artcileHomology modelling of the human adenosine A_2B receptor based on x-ray structures of bovine rhodopsin, the β₂-adrenergic receptor and the human adenosine A_2A receptor, Category: amides-buliding-blocks, the publication is Journal of Computer-Aided Molecular Design (2009), 23(11), 807-828, database is CAplus and MEDLINE.

A three-dimensional model of the human adenosine A_2B receptor was generated by means of homol. modeling, using the crystal structures of bovine rhodopsin, the β₂-adrenergic receptor, and the human adenosine A_2A receptor as templates. In order to compare the three resulting models, the binding modes of the adenosine A_2B receptor antagonists theophylline, ZM241385, MRS1706, and PSB601 were investigated. The A_2A-based model was much better able to stabilize the ligands in the binding site than the other models reflecting the high degree of similarity between A_2A and A_2B receptors: while the A_2B receptor shares about 21% of the residues with rhodopsin, and 31% with the β₂-adrenergic receptor, it is 56% identical to the adenosine A_2A receptor. The A_2A-based model was used for further studies. The model included the transmembrane domains, the extracellular and the intracellular hydrophilic loops as well as the terminal domains. In order to validate the usefulness of this model, a docking anal. of several selective and nonselective agonists and antagonists was carried out including a study of binding affinities and selectivities of these ligands with respect to the adenosine A_2A and A_2B receptors. A common binding site is proposed for antagonists and agonists based on homol. modeling combined with site-directed mutagenesis and a comparison between exptl. and calculated affinity data. The new, validated A_2B receptor model may serve as a basis for developing more potent and selective drugs.

Journal of Computer-Aided Molecular Design published new progress about 264622-53-9. 264622-53-9 belongs to amides-buliding-blocks, auxiliary class GPCR/G Protein,Adenosine Receptor, name is N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide, and the molecular formula is C9H21NO3, Category: amides-buliding-blocks.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Ferretti, Valeria published the artcileA structural study of new potent and selective antagonists to the A2B adenosine receptor, Product Details of C27H29N5O5, the publication is Acta Crystallographica, Section B: Structural Science (2005), B61(5), 569-576, database is CAplus and MEDLINE.

Xanthines, including the natural derivatives theophylline and caffeine, are non-selective antagonists of adenosine. They are able to bind with good affinity to all four adenosine-receptor subtypes A1, A2A, A2B and A3. To develop new drugs with few side effects, over the last few years many efforts have been devoted to the discovery of new adenosine antagonists with enhanced selectivity properties. The present paper reports the crystal structures of five new xanthinic derivatives, which display different affinities and selectivity properties towards the A2B receptor. Besides the crystallog. study, a structural comparison has been made with the calculated geometry of other xanthinic derivatives which are reported to have similar biol. characteristics to understand the structural features controlling their affinity capabilities and selectivity. This structural comparison has been interpreted in the light of a recently published study on the binding of N-benzo[1,3]-dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1-H-pyrazol-3-iloxy]-acetamide to a model of the A2B receptor, which shows the most interesting affinity and selectivity properties.

Acta Crystallographica, Section B: Structural Science published new progress about 264622-53-9. 264622-53-9 belongs to amides-buliding-blocks, auxiliary class GPCR/G Protein,Adenosine Receptor, name is N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide, and the molecular formula is C27H29N5O5, Product Details of C27H29N5O5.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Pejman, Laleh published the artcileThe effect of adenosine A2A and A2B antagonists on tracheal responsiveness, serum levels of cytokines and lung inflammation in guinea pig model of asthma, Formula: C27H29N5O5, the publication is Advanced Pharmaceutical Bulletin (2014), 4(2), 131-138, 8 pp., database is CAplus and MEDLINE.

Nowadays adenosine is specified as an important factor in the pathophysiol. of asthma. For determining the effect of different A2 receptors, in this investigation the effect of single dose of selective adenosine A2A and A2B antagonists (ZM241385 and MRS1706) on different inflammatory parameters; tracheal responsiveness to methacholine and ovalbumin, total and differential cell count in bronchoalveolar lavage (BAL), blood levels of IL-4 and IFN-γ and lung pathol. of guinea pig model of asthma were assessed. All mentioned parameters were evaluated in 2 sensitized groups of guinea pigs pretreated with A2A and A2B antagonists (S+Anta A2A, S+Anta A2B) compared with sensitized (S) and control (C) groups. The tracheal responsiveness to methacholine and OA, total cell and eosinophil and basophil count in BAL, blood IL-4 level and pathol. changes in pretreated group with MRS1706 (S+Anta A2B) was significantly lower than those of sensitized group. In pretreated group with Anta A2A(S+Anta A2A), all the above changes were reversed. These results showed a preventive effect of A2B antagonist (MRS1706) on tracheal responsiveness to methacholine and OA, total and differential cell count in bronchoalveolar lavage, blood cytokines and pathol. changes. Administration of ZM241385, selective A2A antagonist, deteriorated the induction effect of ovalbumin.

Advanced Pharmaceutical Bulletin published new progress about 264622-53-9. 264622-53-9 belongs to amides-buliding-blocks, auxiliary class GPCR/G Protein,Adenosine Receptor, name is N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide, and the molecular formula is C27H29N5O5, Formula: C27H29N5O5.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics