%0 Journal Article %1 Hess2000 %A Hess, S. %A Muller, C. E. %A Frobenius, W. %A Reith, U. %A Klotz, K. N. %A Eger, K. %D 2000 %J J Med Chem %K & A3 Adenine/*chemistry Adenosine Animals Assay CHO Cerebral Corpus Cortex/metabolism Cricetinae Humans Indoles/*chemical P1/*antagonists Proteins/metabolism Purinergic Pyrimidines/*chemical Radioligand Rats Recombinant Relationship Solubility Striatum/metabolism Structure-Activity Water inhibitors/metabolism synthesis/chemistry/metabolism/pharmacology Receptor Cell %N 24 %P 4636-46 %T 7-Deazaadenines bearing polar substituents: structure-activity relationships of new A(1) and A(3) adenosine receptor antagonists %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11101355 %V 43 %X 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.

@article{Hess2000, abstract = {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.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Hess, S. and Muller, C. E. and Frobenius, W. and Reith, U. and Klotz, K. N. and Eger, K.}, biburl = {https://www.bibsonomy.org/bibtex/2251dc2995445bd1801c935c937f87113/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {6c7834401da4e11a8a4cc6f9cae8010c}, intrahash = {251dc2995445bd1801c935c937f87113}, issn = {0022-2623 (Print) 0022-2623 (Linking)}, journal = {J Med Chem}, keywords = {& A3 Adenine/*chemistry Adenosine Animals Assay CHO Cerebral Corpus Cortex/metabolism Cricetinae Humans Indoles/*chemical P1/*antagonists Proteins/metabolism Purinergic Pyrimidines/*chemical Radioligand Rats Recombinant Relationship Solubility Striatum/metabolism Structure-Activity Water inhibitors/metabolism synthesis/chemistry/metabolism/pharmacology Receptor Cell}, month = {Nov 30}, note = {Hess, S Muller, C E Frobenius, W Reith, U Klotz, K N Eger, K In Vitro Research Support, Non-U.S. Gov't United States Journal of medicinal chemistry J Med Chem. 2000 Nov 30;43(24):4636-46.}, number = 24, pages = {4636-46}, shorttitle = {7-Deazaadenines bearing polar substituents: structure-activity relationships of new A(1) and A(3) adenosine receptor antagonists}, timestamp = {2010-12-14T18:20:39.000+0100}, title = {7-Deazaadenines bearing polar substituents: structure-activity relationships of new A(1) and A(3) adenosine receptor antagonists}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11101355}, volume = 43, year = 2000 }