TY - JOUR
T1 - Adenosine receptor binding
T2 - Structure-activity analysis generates extremely potent xanthine antagonists
AU - Bruns, R. F.
AU - Daly, J. W.
AU - Snyder, S. H.
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 1983
Y1 - 1983
N2 - Structure-activity analysis of alkylxanthine derivatives at adenosine receptor binding sites has been employed to design more potent adenosine receptor antagonists. Receptor affinities of xanthines were determined by measuring inhibition of the binding of N6-[3H]cyclohexyladenosine to bovine brain membranes. 1,3-Dipropyl substitutions enhance potency compared to the 1,3-dimethyl substitution in theophylline. An 8-phenyl substituent produces a considerable increase in potency, which is augmented by certain para substitutions on the 8-phenyl ring. Combining an ortho amino with a para-chloro substituent on the 8-phenyl ring affords further increases in potency. Combining all of these substituents results in 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine, a compound of extraordinary receptor affinity, with a K(i) for adenosine A1 receptors of 22 pM. It is 4,000,000 times more potent than xanthine itself and 70,000 times more potent than theophylline.
AB - Structure-activity analysis of alkylxanthine derivatives at adenosine receptor binding sites has been employed to design more potent adenosine receptor antagonists. Receptor affinities of xanthines were determined by measuring inhibition of the binding of N6-[3H]cyclohexyladenosine to bovine brain membranes. 1,3-Dipropyl substitutions enhance potency compared to the 1,3-dimethyl substitution in theophylline. An 8-phenyl substituent produces a considerable increase in potency, which is augmented by certain para substitutions on the 8-phenyl ring. Combining an ortho amino with a para-chloro substituent on the 8-phenyl ring affords further increases in potency. Combining all of these substituents results in 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine, a compound of extraordinary receptor affinity, with a K(i) for adenosine A1 receptors of 22 pM. It is 4,000,000 times more potent than xanthine itself and 70,000 times more potent than theophylline.
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U2 - 10.1073/pnas.80.7.2077
DO - 10.1073/pnas.80.7.2077
M3 - Article
C2 - 6300892
AN - SCOPUS:0345462870
VL - 80
SP - 2077
EP - 2080
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 7 I
ER -