Abstract
Adenosine is an endogenous modulator of a large variety of physiological functions through the interaction with specific cell membrane Gβproteinβcoupled receptors classified as A~1~, A~2A~, A~2B~, and A~3~. Activation of A~3~ receptors has been shown to stimulate phospholipase C and to inhibit adenylate cyclase. A~3~ 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 A~3~ 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 A~3~ antagonists. Herein, we report our past and recent results in the development of tricyclic A~3~ selective antagonists. The pyrazolo[4,3βe]β1,2,4βtriazolo[1,5βc]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 N^5^ position and of substituents at C^9^ and/or at N^8^ pyrazole nitrogen. These studies allowed us to obtain a large variety of compounds which showed affinities in the nanomolar range with human A~3~ adenosine receptors with a high degree of selectivity vs. all other receptors subtypes. Thanks to the introduction of alkylating groups at pβposition of the N^5^βphenylcarbamoyl chain, we succeeded in realizing potent irreversible A~3~ 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 A~3~ affinity and selectivity. Drug Dev. Res. 58:315β329, 2003. Β© 2003 WileyβLiss, Inc.