Pyrimidin-8-on[2,1-f]theophylline-9-alkylcarboxylic acids amides as A1 and A2A adenosine receptor ligands.
Starting from the appropriate esters (1-3), pyrimidin-8-on[2,1-f]theophylline-9-alkylcarboxylic acids amides (4-10) were synthesized and evaluated as hydrochlorides (4a-10a) for their affinity at brain A(1) and A(2A) adenosine receptor subtypes. Radioligand binding assay showed that morpholine-ethyl(-propyl) amide of pyrimidin-8-on[2,1-f]theophylline-9-acetic acid (4a, 5a) exhibited greater affinity and selectivity for A(1) and A(2A) receptors than parent compounds (theophylline and caffeine), with K(i) values: 12.2 and 3.1 microM for A(1) and 1.11 and 5.89 microM for A(2A), respectively. Morpholine-ethyl amide of pyrimidin-8-on[2,1-f]theophylline-9-propanoic acid (6a) and the dimethyl-amino analog (10a) exhibited much lower affinity for A(1) and A(2A) adenosine receptors, with K(i) values, respectively: 53.9 and 72.6 microM for A(1) and 120 and 115 microM for A(2A). Morpholine-propyl amide of pyrimidin-8-on[2,1-f]theophylline-9-propanoic acid (7a) exhibited relatively higher affinity for A(1) adenosine receptor with K(i) value 32.8 microM, comparable to caffeine, but it showed weaker affinity to A(2A) receptor. The variation of affinity at A(1) and A(2A) adenosine receptors depends on the structure of substituent in N9-position of fused tricyclic theophylline derivatives. The most interesting were morpholino-ethyl(-propyl) amides of pyrimidin-8-on[2,1-f]theophylline-9-acetic acid (4a, 5a). The longer alkylene chain (propylene) between amide nitrogen and the basic center (5a) resulted in higher A(1) but lower A(2A) receptor affinity.
Fhid
Omeran
O
Department of Pharmaceutical Chemistry, Collegium Medicum, Jagiellonian University, Medyczna 9, 30-688, Kraków, Poland
Pawlowski
Maciej
M
Jurczyk
Slawomir
S
Muller
Christa E
CE
Schumacher
Britta
B
D000818:Animals; D001921:Brain / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
D002264:Carboxylic Acids; D008024:Ligands; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A