title: A new generation of adenosine receptor antagonists: from di- to trisubstituted aminopyrimidines.
abstract: New adenosine receptor ligands were designed as hybrid structures between previously synthesized substituted dicyanopyridines and aminopyrimidines, yielding two series of cyano-substituted diphenylaminopyrimidines. We were interested in assessing the effect of this substitution pattern on both affinity and intrinsic activity, as the dicyanopyridines comprised both agonists and inverse agonists, whereas the original aminopyrimidines were exclusively inverse agonists. It was found that the new compounds were generally selective for adenosine A(1) receptors, although affinity for the adenosine A(2A) receptor was also noticed for some of the compounds. In a cAMP second messenger assay the compounds behaved as inverse agonists rather than agonists. Among the more A(1) receptor-selective compounds were 5 (LUF6048), 27 (LUF6040) and 53 (LUF6056) with K(i) values of 8.1, 1.2 and 5.7nM, respectively.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, PO Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Jacobus P D
authors.initials: JP
authors.lastname: van Veldhoven
authors.forename: Lisa C W
authors.initials: LC
authors.lastname: Chang
authors.forename: Jacobien K
authors.initials: JK
authors.lastname: von Frijtag Drabbe Künzel
authors.forename: Thea
authors.initials: T
authors.lastname: Mulder-Krieger
authors.forename: Regina
authors.initials: R
authors.lastname: Struensee-Link
authors.forename: Margot W
authors.initials: MW
authors.lastname: Beukers
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000588:Amines; D000242:Cyclic AMP; D006801:Humans; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D000242:Cyclic AMP