title: Selective human adenosine A3 antagonists based on pyrido[2,1-f]purine-2,4-diones: novel features of hA3 antagonist binding.
abstract: Based on our previous results on the potent antagonist effect of 1H,3H-pyrido[2,1-f]purine-2,4-diones at the human A(3) adenosine receptor, new series of this family of compounds have been synthesized and evaluated in radioligand binding studies against the human A(1), A(2A), A(2B), and A(3) receptors. A remarkable improvement in potency, and most noticeable, in selectivity has been achieved, as exemplified by the 3-cyclopropylmethyl-8-methoxy-1-(4-methylbenzyl)-1H,3H-pyrido[2,1-f]purine-2,4-dione (10) that combines a very high affinity at hA(3) (K(i)=2.24 nM), with lack of affinity for the A(1), A(2A), and A(2B) receptors. On the basis of the published hA(3) receptor model (PDB 1OEA), molecular modeling studies, including molecular dynamics (MD) simulations, have been performed to depict the binding mode of the 1 H,3H-pyrido[2,1-f]purine-2,4-diones and to justify the selectivity against the other adenosine receptors. These studies have led to novel features of the cavity where our antagonists are bound so that the cavity is lined by the hydrogen-bonded Gln 167-Asn 250 pair and by the highly conserved Phe 168.
authors.affiliation: Instituto de Química Médica, C.S.I.C. Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Eva-María
authors.initials: EM
authors.lastname: Priego
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Pérez-Pérez
authors.forename: Jacobien K
authors.initials: JK
authors.lastname: von Frijtag Drabbe Kuenzel
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Martín-Santamaría
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D011687:Purines; D011744:Pyrimidinones; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3