7-deazaadenines bearing polar substituents:: Structure-activity relationships of new A1 and A3 adenosine receptor antagonists

A series of 28 new pyrrolo [2,3-d]pyrimidine-4-amines, pyrimido [4,5-b]jndole-4-amines, and tetrahydropyrimido[4,5-b] indole-camines was synthesized and their adenosine receptor affinity determined in radioligand binding assays at rat A(1) and A(2A) adenosine receptors (ARs). Selected compounds were additionally investigated in binding assays at recombinant A(3) ARs. The 2-phenyl residue in (R)-7-(1-methylbenzyl)-2-phenylpyrrolo [2,3-d] pyrimidine-4-amine (ADPEP, 1) and in the corresponding pyrimido [4,5-b]indole (APEPI, 3) could be bioisosterically replaced by heterocyclic rings;such as 2-thienyl and 4-pyridyl. The resulting compounds retained high affinity and selectivity fdr Al ARs. Judging from the investigation of selected compounds, it appears that they are also potent at human Al ARs and selective not only versus A2A ARs but also highly selective versus A(2B) and A(3) ARs. The p-pyridyl-substituted derivatives 11 and 27 (APPPI) may be interesting pharmacological tools due to their fluorescent properties. Pyrrolo[2;3-d] pyrimidine-e-amine derivatives which were simultaneously substituted at N7 and N-4, combining the substitution pattern of ADPEP (1) and DPEAP (2), showed very low affinity for AL ARs. This finding supports our previously published hypothesis of different binding modes for pyrrolopyrimidines, such as ADPEP (1) and DPEAP (2). DPEAP (2), a pyrrolo[2,3-d]pyrimidined-4-amine substituted gt the amino group (N4), was found to exhibit high affinity for human A(3) ARs (K-i = 28 nM), whereas N-4-unsubstituted analogues were inactive. DPEAP (2) and related compounds provide new leads for the development of antagonists for the human A(3) AR.