Abstract
A series of 15 N6-substituted 9-methyladenines have been assessed as antagonists of A2-adenosine receptor-mediated stimulation of adenylate cyclase in membranes of human platelets and rat PC12 cells and of A1-adenosine receptor-mediated inhibition of adenylate cyclases in membranes of rat fat cells and as inhibitors of binding of N6-R-[3H]phenylisopropyladenosine to A1-adenosine receptors in rat brain membranes. N6 substitution can markedly increase the potency of 9-methyladenine at A1 receptors, while having lesser effects or even decreasing potency at. A2 receptors. Effects of N6 substituents on adenosine receptor activity of the 9-methyladenines are reminiscent of effects of N6 substituents on activity of adenosine, suggesting that N6 substituted 9-methyladenines bind to adenosine receptors in the same orientation as do N6-substituted adenosines. N6-Cyclopentyl-9-methyladenine with Ki values at the A1 receptors of 1.3 μM (fat cells) and 0.5 μM (brain) is at least 100-fold more potent than 9-methyladenine (Ki 100 μM, both receptors), while at the A2 receptors KB values of 5 μM (platelets) and 25 μM (PC12 cells) make it 5-fold more potent and equipotent, respectively, compared to 9-methyladenine (KB 24 μM, both receptors). N6-Cyclopentyl and several other N6-alkyl and N6-cycloalkyl analogs are selective for A1 receptors while 9-methyladenine is the most A2 receptor selective antagonist. The N6-R- and N6-S-(1-phenyl-2-propyl)-9-methyladenines, analogous to N6-R- and N6-S-phenylisopropyladenosines, exhibit stereoselectivity at both A1 and A2 receptors. Marked differences in potency of certain N6-substituted 9-methyladenines at the A1 receptors of human platelets and rat PC12 cells provide evidence that these are not identical receptors.
Original language | English (US) |
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Pages (from-to) | 203-208 |
Number of pages | 6 |
Journal | FEBS Letters |
Volume | 215 |
Issue number | 2 |
DOIs | |
State | Published - May 11 1987 |
Keywords
- Adenosine receptor
- Adenylate cyclase
ASJC Scopus subject areas
- Biophysics
- Structural Biology
- Biochemistry
- Molecular Biology
- Genetics
- Cell Biology