1,3,8-trisubstituted xanthines. Effects of substitution pattern upon adenosine receptor A1/A2 affinity.
A series of 11 8-substituted xanthines having three different substitution patterns on the 1- and 3-positions [pattern a (R1 = R3 = CH2CH2CH3), b (R1 = CH2CH2CH3, R3 = CH3), and c (R1 = CH3, R3 = CH2CH2CH3)] was prepared. These compounds were assessed for affinity and selectivity in binding to adenosine A1 and A2 receptors. Compounds with greatest affinity at the A1 receptor had the 1,3-substitution pattern a. With one exception, compounds with pattern a also exhibited the most potent binding at the A2 receptor; however, several compounds with pattern c were equipotent at the A2 receptor with those having pattern a. Additionally, the substituents on the 1- and 3-positions of these 8-substituted xanthines were equally important for determining maximum affinity to the A1 receptor, while the substituent at the 3-position is more important than the substituent at the 1-position for potency at the A2 receptor. As a result of this, it is possible to maximize selectivity for the A1 receptor by choice of the 1- and 3-position substituents. However, the R1/R3 substitution pattern required for maximum A1 selectivity is also dependent upon the substituent in the 8-position in a manner which is not fully understood.
Erickson
R H
RH
Nova Pharmaceutical Corporation, Baltimore, Maryland 21224.
Hiner
R N
RN
Feeney
S W
SW
Blake
P R
PR
Rzeszotarski
W J
WJ
Hicks
R P
RP
Costello
D G
DG
Abreu
M E
ME
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D007202:Indicators and Reagents; D007700:Kinetics; D015394:Molecular Structure; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D007202:Indicators and Reagents; D011983:Receptors, Purinergic; D014970:Xanthines