Analogues of caffeine and theophylline: effect of structural alterations on affinity at adenosine receptors.
A variety of analogues of caffeine and theophylline in which the 1-,3-, and 7-methyl substituents have been replaced with n-propyl, allyl, propargyl, and isobutyl and, in a few cases, with chloroethyl, hydroxyethyl, or benzyl were assessed for potency and selectivity as antagonists at A1- and A2-adenosine receptors in brain tissue. Caffeine and theophylline are nonselective for these receptors. Nearly all of the 22 analogues of caffeine are more potent than caffeine itself at adenosine receptors. Replacement of the 1-methyl moiety with n-propyl, allyl, or propargyl substituent has little effect on potency at the A1 receptor while enhancing potency about 7- to 10-fold at the A2 receptor. 3,7-Di-methyl-1-propylxanthine is only slightly (1.4-fold) more potent than caffeine at the A1 receptor while being 10-fold more potent at the A2 receptor. 1,3-Di-n-propyl-7-methylxanthine is also selective for the A2 receptor, being 8-fold more potent than caffeine at the A1 receptor and 40-fold more potent at the A2 receptor. A number of other caffeine analogues including 3,7-dimethyl-1-n-propylxanthine, 7-allyl-1,3-dimethylxanthine, and 1,3-dimethyl-7-propargylxanthine are also somewhat selective for the A2 receptor. The most potent caffeine analogue was 1,3-di-n-propyl-7-propargylxanthine, which was about 100-fold more potent than caffeine at both A1 and A2 receptors. The 10 theophylline analogues were relatively nonselective except for the 1-ethyl analogue and the 1,3-diallyl analogue, which were selective for the A2 receptor, and the 1,3-di-n-propyl, 1,3-diisobutyl, and 1,3-dibenzyl analogues, which were somewhat selective for the A1 receptor. 1,3-Di-n-propylxanthine was 20-fold more potent than theophylline at the A1 receptor and 5-fold more potent at the A2 receptor.
D000818:Animals; D002110:Caffeine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014970:Xanthines / Q000138:chemical synthesis*
D007202:Indicators and Reagents; D011983:Receptors, Purinergic; D014970:Xanthines; D002110:Caffeine; D013806:Theophylline