Selective human adenosine A3 antagonists based on pyrido2,1-fpurine-2,4-diones: Novel features of hA3 antagonist binding

摘要

Based on our previous results on the potent antagonist effect of 1H,3H-pyrido[2,1-f]purine-2,4-diones at the human A3 adenosine receptor, new series of this family of compounds have been synthesized and evaluated in radioligand binding studies against the human A1, A 2A, A2B, and A3 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 (Ki=2.24 nM), with lack of affinity for the A 1, A2A, and A2B receptors. On the basis of the published hA3 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. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.