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]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 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 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. Pyrrolo[2,3-d]pyrimidine-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 pyrrolo[2,3-d]pyrimidine-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.
Hess
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Pharmaceutical Chemistry, Institute of Pharmacy, University of Leipzig, Bruderstrasse 34, D-04103 Leipzig, Germany. hess@rz.un-leipzig.de
Müller
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Frobenius
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Reith
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Klotz
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Eger
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D000225:Adenine / Q000737:chemistry*; D000818:Animals; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
D007211:Indoles; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D011994:Recombinant Proteins; D014867:Water; D000225:Adenine