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Título

Synthesis, biological activity and molecular docking analysis of new A2A adenosine receptor agonists

AutorRodríguez, Anna M.; Rosell, Gloria CSIC; Bujons, Jordi CSIC ORCID; Gutiérrez-de-Terán, Hugo; Rodríguez, David; Brea, José Manuel; Loza, María Isabel; Guerrero, Ángel CSIC ORCID; Bosch, María Pilar CSIC
Fecha de publicación2010
EditorSpringer Nature
CitaciónPurinergic Signalling
ResumenFollowing a previous work from our group (J. Med. Chem. 2004, 47, 4041–4053), we present herein the synthesis, molecular docking analysis and biological evaluation of new 2-alkylaminoadenosine derivatives as potential agonists for the human A2A adenosine receptor (A2AAR). These derivatives contain an ethyl-substituted tetrazole moiety at the ribose ring, a chiral alkyl group at the vicinal position of the amine and different substituted aromatic systems. Synthesis of the chiral amines has been achieved by enzymatic resolution methodologies. Biological activity of the potential agonists has been evaluated by radioligand binding assays using recombinant human ARs, and by determination of the cAMP production in these receptors expressed in transfected CHO (A1AR), HeLa (A2AAR, A3AR) and HEK-293 (A2BAR) cells. Elucidation of the molecular interactions of these potential agonists was achieved through docking studies using the previously solved X-ray crystallography structure of human A2AAR (Science 2008, 322, 1211–1217). Some compounds displayed a remarkable potency and affinity for A2AAR (Ki 5–56 nM, EC50 2–19 nM) and low or negligible affinity for A1AR, A2BAR and A3AR. Computational simulations suggest a ligand binding mode in agreement with the mutagenesis and structural data available for the A2AAR (J. Med. Chem. 2003, 46, Purinergic Signalling (2010) 6 (Suppl 1):S1–S162 S41 4847–4859), with the phenyl ring oriented in the solvent-exposed extracellular side. New adenosine derivatives with high A2AAR selectivity and potency have been developed. Our results suggest that substitution at the para-position of the phenyl ring by different groups has no significant effect in binding affinity for the human A2AAR.
Versión del editorhttp://www.springerlink.com/content/1573-9538/6/s1/
URIhttp://hdl.handle.net/10261/54036
ISSN1573-9538
E-ISSN1573-9546
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