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N 6 ‐Substituted 9‐methyladenines: A new class of adenosine receptor antagonists
Author(s) -
Ukena D.,
Padgett W.L.,
Hong O.,
Daly J.W.,
Daly D.T.,
Olsson R.A.
Publication year - 1987
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(87)80146-1
Subject(s) - adenosine , class (philosophy) , chemistry , receptor , stereochemistry , adenosine receptor , biochemistry , computer science , agonist , artificial intelligence
A series of 15 N 6 ‐substituted 9‐methyladenines have been assessed as antagonists of A 2 ‐adenosine receptor‐mediated stimulation of adenylate cyclase in membranes of human platelets and rat PC12 cells and of A 1 ‐adenosine receptor‐mediated inhibition of adenylate cyclases in membranes of rat fat cells and as inhibitors of binding of N 6 ‐ R ‐[ 3 H]phenylisopropyladenosine to A 1 ‐adenosine receptors in rat brain membranes. N 6 substitution can markedly increase the potency of 9‐methyladenine at A 1 receptors, while having lesser effects or even decreasing potency at. A 2 receptors. Effects of N 6 substituents on adenosine receptor activity of the 9‐methyladenines are reminiscent of effects of N 6 substituents on activity of adenosine, suggesting that N 6 substituted 9‐methyladenines bind to adenosine receptors in the same orientation as do N 6 ‐substituted adenosines. N 6 ‐Cyclopentyl‐9‐methyladenine with K i values at the A 1 receptors of 1.3 μM (fat cells) and 0.5 μM (brain) is at least 100‐fold more potent than 9‐methyladenine ( K i 100 μM, both receptors), while at the A 2 receptors K B values of 5 μM (platelets) and 25 μM (PC12 cells) make it 5‐fold more potent and equipotent, respectively, compared to 9‐methyladenine ( K B 24 μM, both receptors). N 6 ‐Cyclopentyl and several other N 6 ‐alkyl and N 6 ‐cycloalkyl analogs are selective for A 1 receptors while 9‐methyladenine is the most A 2 receptor selective antagonist. The N 6 ‐ R ‐ and N 6 ‐ S ‐(1‐phenyl‐2‐propyl)‐9‐methyladenines, analogous to N 6 ‐ R ‐ and N 6 ‐ S ‐phenylisopropyladenosines, exhibit stereoselectivity at both A 1 and A 2 receptors. Marked differences in potency of certain N 6 ‐substituted 9‐methyladenines at the A 1 receptors of human platelets and rat PC12 cells provide evidence that these are not identical receptors.