Zusammenfassung
A series of 28 new pyrrolo2,3-dpyrimidine-4-amines, pyrimido4,
5-bindole-4-amines, and tetrahydropyrimido4,5-bindole-4-amines
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-phenylpyrrolo2,3-dpyrimidine-4-amine
(ADPEP, 1) and in the corresponding pyrimido4,5-bindole (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 A(1) ARs. Judging from the investigation
of selected compounds, it appears that they are also potent at human
A(1) ARs and selective not only versus A(2A) 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. Pyrrolo2,3-dpyrimidine-4-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 A(1) ARs. This finding supports our previously published
hypothesis of different binding modes for pyrrolopyrimidines, such
as ADPEP (1) and DPEAP (2). DPEAP (2), a pyrrolo2,3-dpyrimidine-4-amine
substituted at the amino group (N(4)), 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.
Nutzer