- Development and Application of Subtype-Selective Fluorescent Antagonists for the Study of the Human Adenosine A1Receptor in Living Cells
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The adenosine A1 receptor (A1AR) is a G-protein-coupled receptor (GPCR) that provides important therapeutic opportunities for a number of conditions including congestive heart failure, tachycardia, and neuropathic pain. The development of A1AR-selective fluorescent ligands will enhance our understanding of the subcellular mechanisms underlying A1AR pharmacology facilitating the development of more efficacious and selective therapies. Herein, we report the design, synthesis, and application of a novel series of A1AR-selective fluorescent probes based on 8-functionalized bicyclo[2.2.2]octylxanthine and 3-functionalized 8-(adamant-1-yl) xanthine scaffolds. These fluorescent conjugates allowed quantification of kinetic and equilibrium ligand binding parameters using NanoBRET and visualization of specific receptor distribution patterns in living cells by confocal imaging and total internal reflection fluorescence (TIRF) microscopy. As such, the novel A1AR-selective fluorescent antagonists described herein can be applied in conjunction with a series of fluorescence-based techniques to foster understanding of A1AR molecular pharmacology and signaling in living cells.
- Comeo, Eleonora,Trinh, Phuc,Nguyen, Anh T.,Nowell, Cameron J.,Kindon, Nicholas D.,Soave, Mark,Stoddart, Leigh A.,White, Jonathan M.,Hill, Stephen J.,Kellam, Barrie,Halls, Michelle L.,May, Lauren T.,Scammells, Peter J.
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p. 6670 - 6695
(2021/04/12)
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- Bronchospasmolytic activity and adenosine receptor binding of some newer 1,3-dipropyl-8-phenyl substituted xanthine derivatives
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The aldehyde derivatives of 1,3-dipropyl xanthines as described in this paper, constitutes a new series of selective adenosine ligands displaying bronchospasmolytic activity. The effect of substitution at third- and fourth-position of 8-phenyl xanthine ha
- Gumber, Divya,Yadav, Divya,Yadav, Rakesh,Kachler, Sonja,Klotz, Karl Norbert
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p. 600 - 609
(2020/03/23)
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- Ionic liquid mediated one-pot synthesis of 6-aminouracils
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A novel, one-pot synthesis of 6-aminouracils via in situ generated ureas and cyanoacetylureas in the presence of an ionic liquid catalyst, 1,1,3,3-tetramethylguanidine acetate, is described. The catalyst can be recycled for five consecutive runs without loss of activity. The mechanism for the ring closure of cyanoacetylurea to 6-aminouracil is also discussed.
- Chavan, Sunil S.,Degani, Mariam S.
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p. 296 - 299
(2012/03/26)
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- Adenosine A2A receptor-antagonist/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A 2A-D2 receptor heteromers
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Adenosine A2A (A2AR) and dopamine D2 (D2R) receptors mediate the antagonism between adenosinergic and dopaminergic transmission in striatopallidal GABAergic neurons and are pharmacological targets for the treatment of Parkinson's disease.Here, a family of heterobivalent ligands containing a D2R agonist and an A 2AR antagonist linked through a spacer of variable size was designed and synthesized to study A2AR-D2R heteromers. Bivalent ligands with shorter linkers bound to D2R or A2AR with higher affinity than the corresponding monovalent controls in membranes from brain striatum and from cells coexpressing both receptors. In contrast, no differences in affinity of bivalent versus monovalent ligands were detected in experiments using membranes from cells expressing only one receptor. These findings indicate the existence of A2AR-D2R heteromers and of a simultaneous interaction of heterobivalent ligands with both receptors. The cooperative effect derived from the simultaneous interaction suggests the occurrence of A2AR-D2R heteromers in cotransfected cells and in brain striatum. The dopamine/adenosine bivalent action could constitute a novel concept in Parkinson's disease pharmacotherapy.
- Soriano, Aroa,Ventura, Ruben,Molero, Anabel,Hoen, Rob,Casado, Vicent,Corte, Antoni,Fanelli, Francesca,Albericio, Fernando,Lluís, Carmen,Franco, Rafael,Royo, Miriam
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supporting information; experimental part
p. 5590 - 5602
(2010/03/24)
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- Immunosuppressive effects of 8-substituted xanthine derivatives
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The invention relates to a novel use of 8-substituted xanthine derivatives for the manufacture of a medicament for the treatment of auto-immuno disorders.
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Page/Page column 4
(2008/06/13)
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- An expedient method for the synthesis of 6-substituted uracils under microwave irradiation in a solvent-free medium
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Condensation of malonic acid 1 and ureas 2a-f proceeds smoothly in the presence of acetic anhydride 3 under microwave irradiation in solvent-free conditions to give 6-hydroxy-uracils 4 in excellent yields. Under identical conditions, the condensation of cyanoacetic acid 5 and ureas 2a,b,g and h in the presence of acetic anhydride 3, followed by cyclization in the presence of sodium hydroxide affords 6-amino-uracils 6 in high yields. The work-up procedures are simple and products need no purification.
- Devi, Ipsita,Bhuyan, Pulak J.
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p. 5727 - 5729
(2007/10/03)
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- Synthesis, biological and modeling studies of 1,3-di-n-propyl-2,4-dioxo-6- methyl-8-(substituted) 1,2,3,4-tetrahydro [1,2,4]-triazolo [3,4-f]-purines as adenosine receptor antagonists
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A new series of potential adenosine receptor antagonists with a [1,2,4]-triazolo-[3,4-f]-purine structure bearing at the 1 and 3 position n-propyl groups have been synthesized, and their affinities at the four human adenosine receptor subtypes (A1/s
- Pastorin,Bolcato,Cacciari,Kachler,Klotz,Montopoli,Moro,Spalluto
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p. 643 - 651
(2007/10/03)
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- NOVEL XANTHINES HAVING ADENOSINE A1-RECEPTOR ANTAGONIST PROPERTIES
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The subject invention provides 1,3-dipropylxanthines that have an ester function at the 8-position also have potent and specific A1AdoR antagonist properties.
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- Di- or trisubstituted xanthines with neuroleptic properties and composition
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The invention relates to xanthines corresponding to the formula STR1 and physiologically acceptable salts thereof, in which R1 represents C2 -C4 -alkyl, C3 -C4 -isoalkyl, CH2 -(C2 -C3 -alkenyl) or CH2 -(C3 -isoalkenyl); R3 represents C3 -C5 -alkyl, C3 -C5 -isoalkyl, CH2 -(C2 -C4 -alkenyl) or CH2 -(C3 -C4 -isoalkenyl); R8 represents H, methyl or ethyl; with the proviso that (1) when R8 represents H, R1 is allyl and (2) R1 and R3 cannot both represent butyl or allyl at the same time. The compounds show non-specific or anxiolytic sedative activity.
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