N⁶‐Substituted 9‐methyladenines: A new class of adenosine receptor antagonists

Abstract

A series of 15 @substituted 9-methylaaenines have been assessed as antagonists of 4-adenosine receptormediated stimulation of adenylate cyclase in membranes of human platelets and rat PC12 cells and of A,-adenosine receptor-mediated inhibition of adenylate cyclases in membranes of rat fat cells and as inhibitors of binding of N6-R-PHlphenylisopropyladenosine to A,-adenosine receptors in rat brain membranes. N6 substitution can markedly increase the potency of 9-methyladenine at A, receptors, while having lesser effects or even decreasing potency at 4 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 W substituted 9-methyladenines bind to adenosine receptors in the same orientation as do Wsubstituted adenosines. N6-Cyclopentyl-9-methyladenine with K, values at the A, receptors of 1.3 PM (fat cells) and 0.5 PM (brain) is at least lOO-fold more potent than 9-methyladenine (K, 100 RM, both receptors), while at the 4 receptors KB values of 5 PM (platelets) and 25 RM (PC12 cells) make it 5-fold more potent and equipotent, respectively, compared to 9-methyladenine (KB 24 ,uM, both receptors). WCyclopentyl and several other Walkyl and Wcycloalkyl analogs are selective for A, receptors while 9-methyladenine is the most 4 receptor selective antagonist. The P-R-and W-S(l-phenyl-2-propyl)-9-methyladenines, analogous to P-R-and &Y&phenylisopropyladenosines, exhibit stereoselectivity at both A, and 4 receptors.Marked differences in potency of certain M-substituted 9-methyladenines at the 4 receptors of human platelets and rat PC12 cells provide evidence that these are not identical receptors.

Non-xanthine heterocycles: Activity as antagonists of A1 and A2-adenosine receptors

“…The effects of different N 6 -substituents on activity of 9-methyl-adenines as adenosine receptor antagonists and the effects of the same N 6 -substituents on activity of adenosines as agonists are similar, suggesting that the binding domain for N 6 -substituents of adenosine and the N 6 -substituents of 9-methyladenines are probably the same for both classes of compounds [14]. Certain N 6 -substituted 9-methyladenines (IIIb) are more potent at A 1 than at A 2 receptors, whereas 9-methyladenine (IIIa) is more potent at A 2 receptors (Table 1).…”

“…Discovered during screening of a wide range of compounds as adenosine antagonists [10], the activity of 9-methyladenine (IIIa) has now been found to be enhanced markedly at A 1 receptors by the presence of N 6 -substituents [14]. The effects of different N 6 -substituents on activity of 9-methyl-adenines as adenosine receptor antagonists and the effects of the same N 6 -substituents on activity of adenosines as agonists are similar, suggesting that the binding domain for N 6 -substituents of adenosine and the N 6 -substituents of 9-methyladenines are probably the same for both classes of compounds [14].…”

“…An analogy between the three pyrazolopyridines (Ia, Ib, Ic), which contain a substituted amine moiety on the 6-membered pyridine ring, and 9-methyladenines (IIIb) that contain a similar amine moiety on the 6-membered pyrimidine ring, is an attractive one. N 6 -Substituted 9-methyladenines have been proposed to bind to adenosine receptors in the same orientation as N 6 -substituted adenosines [14].…”

“…Other classes of heterocyclic compounds exhibit antagonist activity at adenosine receptors. These include: 9-methyladenines [10,14], various pyrazolopyridines (etazolate, cartazolate, tracazolate) [15][16][17][18], various pyrazolopyrimidines [19,20], imidazopyrazines [21], a phenyl-substituted pyrazoloquinoline (CGS 8216) [22,23], a furyl-sub-stituted triazoloquinazoline (CGS 15943a) [24], a triazolopyridazine (CL218872) [15], various mesoionic analogs of xanthines [25], pteridin-2,4-diones (lumazine) and benzopteridin-2,4-diones [10,26], β-carbolines [15,27], barbiturates [28,29] and dibenzazepines (carbamazepine) [30][31][32][33]. A phenylaminoimidazoline, clonidine, has been reported to antagonize adenosine responses in physiological experiments [34].…”

2′,3′-Dideoxy-N6-cyclohexyladenosine: an adenosine derivative with antagonist properties at adenosine receptors

“…However, much less is known about the requirements foragonist activity at the A 1 receptor. Sturlies with adenine (Ebert and Schwabe, 1973), 9-substituted adenine derivatives (Ukena et al, 1987) and ribose-modified adenosine analogues (Trost and Stock, 1977;Taylor et al, 1986) have pointed to the importance of the ribose moiety both for binding affinity and agonist effects .. In the present study we report that removal of the 2'-and 3' -hydroxy groups of the potent full A 1 receptor agonist, N 6 -cyclohexyladenosine (CHA), is sufficient to completely abolish its agonist activity.…”