TY - DATA T1 - Isoquinoline and Quinazoline Urea Analogues as Antagonists for the Human Adenosine A3 Receptor PY - 2000/05/11 AU - Jacqueline E. van Muijlwijk-Koezen AU - Henk Timmerman AU - Henk van der Goot AU - Wiro M. P. B. Menge AU - Jacobien Frijtag von Drabbe Künzel AU - Miriam de Groote AU - Adriaan P. IJzerman UR - https://acs.figshare.com/articles/journal_contribution/Isoquinoline_and_Quinazoline_Urea_Analogues_as_Antagonists_for_the_Human_Adenosine_A_sub_3_sub_Receptor/3679440 DO - 10.1021/jm000002u.s001 L4 - https://ndownloader.figshare.com/files/5769228 KW - adenosine receptor affinities KW - substituent KW - 3 Receptor Isoquinoline KW - VUF KW - K i value KW - phenyl KW - quinazoline urea derivatives KW - 3 receptor KW - 3 receptor assay KW - 3 receptor affinity KW - 3 receptor antagonist KW - radioligand binding assays KW - Quinazoline Urea Analogues N2 - Isoquinoline and quinazoline urea derivatives were found to bind to human adenosine A3 receptors. Series of N-phenyl-N‘-quinazolin-4-ylurea derivatives and N-phenyl-N‘-isoquinolin-1-ylurea derivatives were synthesized and tested in radioligand binding assays on their adenosine receptor affinities. A structure−affinity analysis indicated that on the 2-position of the quinazoline ring or the equivalent 3-position of the isoquinoline ring a phenyl or heteroaryl substituent increased the adenosine A3 receptor affinity in comparison to unsubstituted or aliphatic derivatives. Furthermore, the structure−affinity relationship of substituted phenylurea analogues was investigated. Substituents such as electron-withdrawing or electron-donating groups were introduced at different positions of the benzene ring to probe electronic and positional effects of substitution. Substitution on the 3- or 4-position of the phenyl ring decreased the adenosine A3 receptor affinity. Substitution at position 2 with an electron-donating substituent, such as methyl or methoxy, increased human adenosine A3 receptor affinity, whereas substitution on the 2-position with an electron-withdrawing substituent did not influence affinity. Combination of the optimal substituents in the two series had an additive effect, which led to the potent human adenosine A3 receptor antagonist N-(2-methoxyphenyl)-N‘-(2-(3-pyridyl)quinazolin-4-yl)urea (VUF5574, 10a) showing a Ki value of 4 nM and being at least 2500-fold selective vs A1 and A2A receptors. Compound 10a competitively antagonized the effect of an agonist in a functional A3 receptor assay, i.e., inhibition of cAMP production in cells expressing the human adenosine A3 receptor; a pA2 value of 8.1 was derived from a Schild plot. In conclusion, compound 10a is a potent and selective human adenosine A3 receptor antagonist and might be a useful tool in further characterization of the human A3 receptor. ER -