A series of 1,3-dipropylxanthines were prepared with a variety of substituents at the 8-position. These included 8-aryl and 8-cycloalkyl groups. Polar carboxylate and carboxamide moieties were introduced as aryl substituents to increase water solubility. 1,3-Dipropyl-8-[2-hydroxy-4-[(carboxymethyl)oxy]phenyl]xanthine provided a functionalized congener with high potency (Ki = 37 nM) and selectivity (54-fold) for A1-adenosine receptors. This congener was used for preparation of a series of other analogues, some with higher potency and some with higher selectivity. 8-Cyclopentyl- and 8-cyclohexyl-1,3-dipropylxanthines were both very potent (Ki = 1-1.5 nM) and selective for A1 receptors, while 8-cycloalkylmethyl analogues were 10-fold less potent, but still very selective for A1 receptors. 8-Piperidinyl and 8-pyrazinyl analogues had very low activities as adenosine receptor antagonists.

A variety of non-xanthine heterocycles were found to be antagonists of binding of [ 3 H]phenylisopropyladenosine to rat brain A 1 -adenosine receptors and of activation of adenylate cyclase via interaction of N-ethylcarboxarnidoadenosine with A 2 -adenosine receptors in human platelet and rat pheochromocytoma cell membranes. The pyrazolopyridines tracazolate, cartazolate and etazolate were several fold more potent than theophylline at both A 1 -and A 2 -adenosine receptors. The pyrazolopyridines, however, were still many fold less potent than 8-phenyltheophylline and other 8-phenyl-1,3-dialkylxanthines. A structurally related N 6 -substituted 9-methyladenine was also a potent adenosine antagonist with selectivity for A 1 receptors. None of several aryl-substituted heterocycles, including a thiazolopyrimidine, imidazopyridines, benzimidazoles, a pyrazoloquinoline, a mesoionic xanthine analog and a triazolopyridazine exhibited the high potency typical of 8-phenyl-1,3-dialkylxanthines. A furyl-substituted triazoloquinazoline was very potent at both A 1 and A 2 receptors. A pteridin-2,4-dione, 1,3-dipropyllumazine, was somewhat less potent than theophylline at A 1 -and A 2 -adenosine receptors, whereas 1,3-dimethyllumazine was much less potent. A benzopteridin-2,4-dione, alloxazine, was somewhat more potent than theophylline. Other heterocycles with antagonist activity were the dibenzazepine carbamazepine and β-carboline-3-ethyl carboxylate. The phenylimidazoline clonidine had no activity, whereas a related dihydroxyphenylimidazoline was a weak noncompetitive adenosine antagonist.Xanthines, such as theophylline, caffeine and various 8-aryl-1,3-dialkylxanthines, have been widely used as antagonists of A 1 and A 2 -adenosine receptors [1]. The 8-aryl-1,3-dialkylxanthines are very potent at both subclasses of adenosine receptors [2][3][4][5][6][7][8][9][10][11]. Certain 8-aryl-1,3-dipropylxanthines exhibit selectivity for A 1 receptors [4,8,9] and certain caffeine analogs exhibit some selectivity for A 2 receptors [12,13]. 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].The non-xanthine adenosine antagonists have been largely neglected in behavioral and physiological studies, and little is known of structure-activity relationships within such METHODS MaterialsThe sources from which we obtained our mat...

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.

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