共查询到5条相似文献,搜索用时 0 毫秒
1.
Flavia Varano Daniela Catarzi Matteo Falsini Diego Dal Ben Michela Buccioni Gabriella Marucci Rosaria Volpini Vittoria Colotta 《Bioorganic & medicinal chemistry letters》2019,29(4):563-569
This paper describes the synthesis of novel 7-amino-thiazolo[5,4-d]pyrimidines bearing different substituents at positions 2, 5 and 7 of the thiazolopyrimidine scaffold. The synthesized compounds 2–27 were evaluated in radioligand binding (A1, A2A and A3) and adenylyl cyclase activity (A2B and A2A) assays, in order to evaluate their affinity and potency at human adenosine receptor subtypes. The current study allowed us to support that affinity and selectivity of 7-amino-thiazolo[5,4-d]pyrimidine derivatives towards the adenosine receptor subtypes can be modulated by the nature of the groups attached at positions 2, 5 and 7 of the bicyclic scaffold. To rationalize the hypothetical binding mode of the newly synthesized compounds, we also performed docking calculations in human A2A, A1 and A3 structures. 相似文献
2.
Maria Letizia Trincavelli Chiara Giacomelli Simona Daniele Sabrina Taliani Barbara Cosimelli Sonia Laneri Elda Severi Elisabetta Barresi Isabella Pugliesi Giovanni Greco Ettore Novellino Federico Da Settimo Claudia Martini 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Among adenosine receptors (ARs) the A2B subtype exhibits low affinity for the endogenous agonist compared with the A1, A2A, and A3 subtypes and is therefore activated when concentrations of adenosine increase to a large extent following tissue damages (e.g. ischemia, inflammation). For this reason, A2B AR represents an important pharmacological target.Methods
We evaluated seven 1-benzyl-3-ketoindole derivatives (7–9) for their ability to act as positive or negative allosteric modulators of human A2B AR through binding and functional assays using CHO cells expressing human A1, A2A, A2B, and A3 ARs.Results
The investigated compounds behaved as specific positive or negative allosteric modulators of human A2B AR depending on small differences in their structures. The positive allosteric modulators 7a,b and 8a increased agonist efficacy without any effect on agonist potency. The negative allosteric modulators 8b,c and 9a,b reduced agonist potency and efficacy.Conclusions
A number of 1-benzyl-3-ketoindole derivatives were pharmacologically characterized as selective positive (7a,b) or negative (8c, 9a,b) allosteric modulators of human A2B AR.General significance
The 1-benzyl-3-ketoindole derivatives 7–9 acting as positive or negative allosteric modulators of human A2B AR represent new pharmacological tools useful for the development of therapeutic agents to treat pathological conditions related to an altered functionality of A2B AR. 相似文献3.
M. B. Emerit S. El Mestikawy H. Gozlan J. M. Cossery R. Besselievre A. Marquet M. Hamon 《Journal of neurochemistry》1987,49(2):373-380
The synthesis of a tritiated derivative of the 5-HT1A photoaffinity probe 8-methoxy-2-[N-n-propyl, N-3-(2-nitro-4-azidophenyl)aminopropyl]aminotetralin ([3H]8-methoxy-3'-NAP-amino-PAT) allowed the use of this probe for attempting the irreversible labeling of specific binding sites in rat brain membranes. Sodium dodecyl-sulfate-polyacrylamide gel electrophoresis of proteins solubilized from hippocampal microsomal membranes that had been incubated with 20 nM [3H]8-methoxy-3'-NAP-amino-PAT under UV light revealed a marked incorporation of 3H label into a 63-kilodalton protein termed PI. As expected of a possible correspondence between PI and 5-HT1A receptor binding sites, 3H labeling by the photoaffinity probe could be prevented by selective 5-HT1A ligands such as 8-hydroxy-2-(di-n-propylamino)tetralin, ipsapirone, buspirone, and gepirone and by N-ethylmaleimide, but not by the 5-HT2 antagonist ketanserin, noradrenaline- and dopamine-related drugs, monoamine oxidase inhibitors, and chlorimipramine. Furthermore, the regional and subcellular distributions of PI were identical to those of specific 5-HT1A binding sites. These results indicated that the binding subunit of the 5-HT1A receptor is a 63-kilodalton protein with a functionally important sulfhydryl group(s). 相似文献
4.
Kumar TS Mishra S Deflorian F Yoo LS Phan K Kecskés M Szabo A Shinkre B Gao ZG Trenkle W Jacobson KA 《Bioorganic & medicinal chemistry letters》2011,21(9):2740-2745
Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A2A adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The conjugates included an ester, carboxylic acid and amines (for amide condensation), an alkyne (for click chemistry), a fluoropropyl group (for 18F incorporation), and fluorophore reporter groups (e.g., BODIPY conjugate 14, Ki 15 nM). The potent and A2AAR-selective N-aminoethylacetamide 7 and N-[2-(2-aminoethyl)-aminoethyl]acetamide 8 congeners were coupled to polyamidoamine (PAMAM) G3.5 dendrimers, and the multivalent conjugates displayed high A2AAR affinity. Theoretical docking of an AlexaFluor conjugate to the receptor X-ray structure highlighted the key interactions between the heterocyclic core and the binding pocket of the A2AAR as well as the distal anchoring of the fluorophore. In conclusion, we have synthesized a family of high affinity functionalized congeners as pharmacological probes for studying the A2AAR. 相似文献
5.
A2A adenosine receptor (A2AR), P2Y1 receptor (P2Y1R) and P2Y12 receptor (P2Y12R) are predominantly expressed on human platelets. The individual role of each of these receptors in platelet aggregation has been actively reported. Previously, hetero-oligomerization between these three receptors has been shown to occur. Here, we show that Ca2+ signaling evoked by the P2Y1R agonist, 2-methylthioladenosine 5’ diphosphate (2MeSADP) was significantly inhibited by the A2AR antagonist (ZM241385 and SCH442416) and the P2Y12R antagonist (ARC69931MX) using HEK293T cells expressing the three receptors. It was confirmed that inhibition of P2Y1R signaling by A2AR and P2Y12R antagonists was indeed mediated through A2AR and P2Y12R using 1321N1 human astrocytoma cells which do not express P2Y receptors. We expect that intermolecular signal transduction and specific conformational changes occur among components of hetero-oligomers formed by these three receptors. 相似文献