Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives: A new pharmacological tool for the characterization of the human A(3) adenosine receptor

Adenosine regulates many physiological functions by interaction with four different G-protein-coupled receptors classified as A1, A2A, A2B, and A3. While adenosine A1 and A2A receptor subtypes have been pharmacologically characterized through the use of selective ligands, the A2B and A3 adenosine receptor subtypes are presently under study in order to better understand their physio-pathological functions. In particular, activation of adenosine A3 receptors has been shown to stimulate phospholipase C and D and to inhibit adenylate cyclase. Activation of A3 adenosine receptors also causes the release of inflammatory mediators such as histamine from mast cells, which are responsible for processes such as inflammation and hypotension. For these reasons, it has been suggested that A3 adenosine receptor antagonists can be considered potential drugs for the treatment of asthma and inflammation. In the last few years different classes of heterocyclic compounds have been identified as A3 adenosine antagonists, but none of the tested compounds showed significant selectivity for A3 adenosine receptor subtype. Herein, we report our recent results on a class of pyrazolo[4,3-e]l,2,4-triazolo[1,5-c]pyrimidine derivatives as a new class of potent and selective human A3 adenosine receptor antagonists. The full characterization of the first high-affinity radioligand antagonist for this receptor subtype, designated [3H] MRE3008F20, is briefly summarized. © 2001 Wiley-Liss, Inc.