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

Abstract

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...

Limiting Activity at β1-Subunit-Containing GABAA Receptor Subtypes Reduces Ataxia

“…1). Second, tracazolate levels at its AD 50 value are associated with 270% enhancement of ␣ 1 ␤ 1 ␥ 2 GABA A Rs, which may result from its opposing action mediated by adenosine A 1 and A 2 receptors (Daly et al, 1988). Tracazolate is an antagonist of adenosine A 1 and A 2 receptors, with micromolar potency where it is predicted to promote arousal and wakefulness (Van Dort et al, 2009).…”

Novel therapeutics acting via purine receptors

“…For this reason, it would be desirable to develop a selective, potent, and bioavailable non-xanthine adenosine antagonist. A number of classes of non-xanthine adenosine antagonists have been discovered [32]. Of these, CGS 15943A, 14 ( Fig.…”

Survey of Nonxanthine Derivatives as Adenosine Receptor Ligands

“…8 We have found that the presence of chained alkyl groups (e.g. isopropyl) at the 6-and 7-positions enhance the potency of binding to A 1 receptors in this series.…”

“…1). Although xanthines are the classical adenosine antagonists, numerous classes of nonxanthine antagonists, 1,8 mainly fused nitrogen-containing heterocyclic structures, have been reported. Xanthines have, however, proven to be either inactive at cloned rat A 3 receptors, or relatively inactive at the sheep and human cloned A 3 receptors.…”