RESUMO
Three novel nucleosides 1, 2, and 3 were prepared that contained side chains at the 2-position of adenosine. Compound 1 was shown to be the most selective A2a receptor agonist reported to date having an A1/A2 ratio of 2400. In addition, compound 1 was shown to reduce blood pressure in rats and dogs with only minimal effects on heart rate.
Assuntos
Adenosina/análogos & derivados , Nucleosídeos de Purina/síntese química , Agonistas do Receptor Purinérgico P1 , Adenosina/síntese química , Adenosina/química , Adenosina/metabolismo , Adenosina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Técnicas In Vitro , Nucleosídeos de Purina/química , Nucleosídeos de Purina/metabolismo , Nucleosídeos de Purina/farmacologia , Ratos , Receptor A2A de AdenosinaRESUMO
Several 8-substituted 1,3-dipropylxanthines were synthesized, and their receptor binding affinities at adenosine A1 and A2 receptors were measured. When enantiomeric pairs of compounds were examined, the R enantiomers were significantly more potent than the corresponding S enantiomers. The most potent compound at the A1 receptor was (R)-3,7-dihydro-8-(1-methyl-2-phenylethyl)-1,3-dipropyl-1H-purine-2,6-di one (5a; MDL 102,503), whose Ki value at the A1 receptor was 6.9 nM. However, a more selective compound was (R)-3,7-dihydro-8-(1-phenylpropyl)-1,3-dipropyl-1H-purine-2,6-dione (5d; MDL 102,234), which had a Ki value of 23.2 nM at the A1 receptor and an A2/A1 ratio of 153.
Assuntos
Antagonistas de Receptores Purinérgicos P1 , Xantinas/síntese química , Sítios de Ligação/efeitos dos fármacos , Receptores Purinérgicos P1/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Xantinas/química , Xantinas/farmacologiaRESUMO
Two modes of tethering a chiral (phenylisopropyl)amino substituent in pyrazolo[3,4-d]pyrimidines and purines have been explored. One mode gave (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-5- propoxy-3H-imidazo[1,2-c]pyrazolo-[4,3-e]pyrimidine (12a) and its corresponding R-enantiomer 12b, which were selective for A2 and A1 adenosine receptors, respectively. The corresponding diimidazo[1,2-c:4',5'-e]pyrimidines 12e and 12f were analogously selective. This is the first example where a single chiral recognition unit provides enantiomers with opposite selectivities for adenosine receptors. The second mode gave (2S-trans)-2,7-dihydro-2-methyl-3,7-diphenyl-5- propoxy-3H-imidazo[1,2-c]-pyrazolo[4,3-e]pyrimidine (12c) and its corresponding R-enantiomer 12d. Compounds 12c and 12d were significantly less potent than 12a and 12b at A1 receptors, and were nonselective.