| Abstract
| - Isoquinoline and quinazoline urea derivatives were found to bind to human adenosine A3receptors. 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 theiradenosine receptor affinities. A structure−affinity analysis indicated that on the 2-position ofthe quinazoline ring or the equivalent 3-position of the isoquinoline ring a phenyl or heteroarylsubstituent increased the adenosine A3 receptor affinity in comparison to unsubstituted oraliphatic derivatives. Furthermore, the structure−affinity relationship of substituted phenylureaanalogues was investigated. Substituents such as electron-withdrawing or electron-donatinggroups were introduced at different positions of the benzene ring to probe electronic andpositional effects of substitution. Substitution on the 3- or 4-position of the phenyl ring decreasedthe adenosine A3 receptor affinity. Substitution at position 2 with an electron-donatingsubstituent, such as methyl or methoxy, increased human adenosine A3 receptor affinity,whereas substitution on the 2-position with an electron-withdrawing substituent did notinfluence affinity. Combination of the optimal substituents in the two series had an additiveeffect, 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 atleast 2500-fold selective vs A1 and A2A receptors. Compound 10a competitively antagonizedthe effect of an agonist in a functional A3 receptor assay, i.e., inhibition of cAMP production incells expressing the human adenosine A3 receptor; a pA2 value of 8.1 was derived from a Schildplot. In conclusion, compound 10a is a potent and selective human adenosine A3 receptorantagonist and might be a useful tool in further characterization of the human A3 receptor.
|
