Premium
Selective Human Adenosine A 3 Antagonists based on Pyrido[2,1‐ f ]purine‐2,4‐diones: Novel Features of hA 3 Antagonist Binding
Author(s) -
Priego EvaMaría,
PérezPérez MaríaJesús,
von Frijtag Drabbe Kuenzel Jacobien K.,
de Vries Henk,
IJzerman Adriaan P.,
Camarasa MaríaJosé,
MartínSantamaría Sonsoles
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700173
Subject(s) - stereochemistry , chemistry , adenosine receptor , antagonist , purine , receptor , adenosine , molecular model , selectivity , protein data bank (rcsb pdb) , radioligand , hydrogen bond , binding site , enzyme , biochemistry , molecule , agonist , catalysis , organic chemistry
Based on our previous results on the potent antagonist effect of 1 H ,3 H ‐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)‐1 H ,3 H ‐pyrido[2,1‐f]purine‐2,4‐dione ( 10 ) that combines a very high affinity at hA 3 ( K i =2.24 n M ), 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.