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Isoquinoline and Quinazoline Urea Analogues as Antagonists for the Human Adenosine A3 Receptor

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journal contribution
posted on 11.05.2000 by Jacqueline E. van Muijlwijk-Koezen, Henk Timmerman, Henk van der Goot, Wiro M. P. B. Menge, Jacobien Frijtag von Drabbe Künzel, Miriam de Groote, Adriaan P. IJzerman
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.