Recent developments in the field of A3 adenosine receptor antagonists

Adenosine is an endogenous modulator of a large variety of physiological functions through the interaction with specific cell membrane G‐protein‐coupled receptors classified as A1, A2A, A2B, and A3. Activation of A3 receptors has been shown to stimulate phospholipase C and to inhibit adenylate cyclase. A3 agonists also cause stimulation of phospholipase D and the release of inflammatory mediators, such as histamine from mast cells, which are responsible for inflammation and hypotension. For these reasons, the clinical use of A3 adenosine receptors antagonists for the treatment of asthma and inflammatory disease has been suggested. Recent studies also indicated a possible employment of these derivatives as antitumor agents. Different classes of polyheterocyclic compounds have been identified as potent A3 antagonists. Herein, we report our past and recent results in the development of tricyclic A3 selective antagonists. The pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine nucleus has especially been 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 N8 pyrazole nitrogen. These studies allowed us to obtain a large variety of compounds which showed affinities in the nanomolar range with human A3 adenosine receptors with a high degree of selectivity vs. all other receptors subtypes. Thanks to the introduction of alkylating groups at p‐position of the N5‐phenylcarbamoyl chain, we succeeded in realizing potent irreversible A3 adenosine antagonists. Finally, the replacement of the phenyl nucleus of carbamoyl function with a pyridine ring conferred water solubility to the corresponding derivatives, which are also characterized by high levels of A3 affinity and selectivity. Drug Dev. Res. 58:315–329, 2003.