Xanthines with C8 chiral substituents as potent and selective adenosine A1 antagonists.
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.
Peet
N P
NP
Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Lentz
N L
NL
Dudley
M W
MW
Ogden
A M
AM
McCarty
D R
DR
Racke
M M
MM
D001665:Binding Sites / Q000187:drug effects; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; C084853:MDL 102234