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Vol. 57, Issue 5, 968-975, May 2000

[3H]MRE 3008F20: A Novel Antagonist Radioligand for the Pharmacological and Biochemical Characterization of Human A3 Adenosine Receptors

Katia Varani, Stefania Merighi, Stefania Gessi, Karl-Norbert Klotz, Edward Leung, Pier Giovanni Baraldi, Barbara Cacciari, Romeo Romagnoli, Giampiero Spalluto, and Pier Andrea Borea

Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, Italy (K.V., S.M., S.G., P.A.B.); Institut für Pharmakologie und Toxikologie, Universität Würzburg, Germany (K.-N.K.); Medco Research, Research Triangle Park, North Carolina (E.L.); Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., B.C., R.R.); and Department of Pharmaceutical Sciences, University of Trieste, Italy (G.S.)

The lack of a radiolabeled selective A3 adenosine receptor antagonist is a major drawback for an adequate characterization of this receptor subtype. This paper describes the pharmacological and biochemical characterization of the tritiated form of a new potent A3 adenosine receptor antagonist, the pyrazolo triazolo pyrimidine derivative [3H]5N-(4-methoxyphenylcarbamoyl)amino-8-propyl-2-(2-furyl)pyrazolo[4,3-e] -1,2,4- triazolo[1,5-c]pyrimidine ([3H]MRE 3008F20). [3H]MRE 3008F20 bound specifically to the human adenosine A3 receptor expressed in CHO cells (hA3CHO), and saturation analysis revealed a single high affinity binding site, KD = 0.80 ± 0.06 nM, with a Bmax = 300 ± 33 fmol/mg protein. This new ligand displayed high selectivity (1294-, 165-, and 2471-fold) in binding assay to human A3 versus A1, A2A, and A2B receptors, respectively, and binds to the rat A3 receptors with a Ki > 10 µM. The pharmacological profile of [3H]MRE 3008F20 binding to hA3CHO cells was evaluated using known adenosine receptor agonists and antagonists with a rank order of potency consistent with that typically found for interactions with the A3 adenosine receptors. In the adenylyl cyclase assay the same compounds exhibited a rank order of potency identical with that observed in binding experiments. Thermodynamic data indicated that [3H]MRE 3008F20 binding to hA3CHO is entropy- and enthalpy-driven in agreement with the typical behavior of other adenosine antagonists to A1 and A2A receptors. These results show that [3H]MRE 3008F20 is the first antagonist radioligand with high affinity and selectivity for the human A3 adenosine receptor and may be used to investigate the physiopathological role of A3 adenosine receptors.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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