New Modulators of A3 and A2B Adenosine Receptors

Adenosine, an endogenous modulator of a wide range of biological functions in the nervous, cardiovascular, renal, and immune systems, interacts with at least four cell surface receptor subtypes classified as A1, A2A, A2B and A3.1 Clarification of the role of adenosine and its receptors in cancer development may hold great promise for the chemotherapeutic treatment of patients affected by malignancies.2 Different classes of compounds with non-xanthine structures have been reported to be A3 adenosine receptor antagonists.3 The pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine nucleus has been largely investigated by our group. Our interests were focused on the effects of substitution of the phenyl ring of the arylcarbamoyl moiety at N5 position and of substituents at C9 and/or at N7-N8 pyrazole nitrogens. These studies allowed us to obtain a large variety of compounds which showed affinities in the nanomolar range to human A2A or A3 adenosine receptors with high degree of selectivity.3 Compounds presenting an additional fused ring on the xanthine nucleus have been reported to exhibit antagonistic activity with various levels of affinity and selectivity towards the four adenosine receptors subtypes.4 We evaluated the effect of the introduction of a benzyl and a propyl at the 1 and 3 positions, respectively, in a new series of 7-aryl/alkyl-1H,6H-pyrrolo[2,1-f]purine-2,4-diones and 7-aryl/alkyl-1H,8H-imidazo[2,1-f]purine-2,4-diones,5 among which, very potent and selective A3 receptors antagonists have been identified. In particular 1-benzyl-7-methyl-3-propyl-1H,8H-imidazo[2,1-f]purine-2,4-dione, shows a subnanomolar affinity with a noteworthy selectivity versus the other adenosine receptors subtypes (Ki (hA3) = 0.8 nM, Ki (hA1/hA3) = 3163, Ki (hA2A/hA3) > 6250, IC50 (hA2B)/Ki (hA3) = 2570). Colotta et al. directed much effort toward the study of adenosine receptor antagonists investigating the 2-arylpyrazolo[3,4-c]-quinoline nucleus.6 In light of the reported activity profile, we decided to synthesize the structural isomers, 2-arylpyrazolo[4,3-c]quinolines,7 some of which showed high A3 receptor affinity and complete selectivity (2-p-tolyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-one; KihA1, KihA2A, EC50hA2B>1000 nM, KihA3= 9 nM). In the search for improved selective A2B antagonists for the treatment of asthma,8 we synthesized a variety of new 1,3-dipropyl-8-heterocyclic-substituted xanthines.9 We introduced several heterocycles, such as pyrazole, isoxazole, pyridine and pyridazine at the 8-position of the xanthine nucleus. We have also investigated different spacers (substituted acetamide, oxyacetamide and urea moieties) on the heterocycle introduced. Some of the synthesized C8-substituted xanthines showed high affinity at A2B receptor subtype and very good selectivity (N-benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]-acetamide; hA2B = 5.5 nM, hA1, hA2A, hA3 > 1000).