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]indole-4-amines, and tetrahydropyrimido[4,5-b]indole-4-amines was synthesized and their adenosine receptor affinity determined in radioligand binding assays at rat A1 and A2A adenosine receptors (ARs). Selected compounds were additionally investigated in binding assays at recombinant A3 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 for A1 ARs. Judging from the investigation of selected compounds, it appears that they are also potent at human A1 ARs and selective not only versus A2A ARs but also highly selective versus A2B and A3 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-4-amine derivatives which were simultaneously substituted at N7 and N4, combining the substitution pattern of ADPEP (1) and DPEAP (2), showed very low affinity for A1 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]pyrimidine-4-amine substituted at the amino group (N4), was found to exhibit high affinity for human A3 ARs (K i = 28 nM), whereas N4-unsubstituted analogues were inactive. DPEAP (2) and related compounds provide new leads for the development of antagonists for the human A3 AR.