7-deazaadenines bearing polar substituents: Structure-activity relationships of new A(1) and A(3) adenosine receptor antagonists

A series of 28 new pyrrolo [2,3-d]pyrimidine-4-amines, pyrimido [4,5-b]jndo le-4-amines, and tetrahydropyrimido[4,5-b] indole-camines was synthesized a nd their adenosine receptor affinity determined in radioligand binding assa ys 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] pyrimidin e-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-thi enyl and 4-pyridyl. The resulting compounds retained high affinity and sele ctivity fdr Al ARs. Judging from the investigation of selected compounds, i t 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-p yridyl-substituted derivatives 11 and 27 (APPPI) may be interesting pharmac ological tools due to their fluorescent properties. Pyrrolo[2;3-d] pyrimidi ne-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 hy pothesis of different binding modes for pyrrolopyrimidines, such as ADPEP ( 1) and DPEAP (2). DPEAP (2), a pyrrolo[2,3-d]pyrimidined-4-amine substitute d 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. DPE AP (2) and related compounds provide new leads for the development of antag onists for the human A(3) AR.