The adenosine A(2B) receptor is the least well characterized of the four known adenosine receptor subtypes because of the absence of potent, selective agonists. Here, we present five non-adenosine agonists. Among them, 2-amino-4-(4-hydroxyphenyl)-6-(1H-imidazol-2-ylmethylsulfanyl)pyridine-3,5-dicarbonitrile, 17, LUF5834, is a high-efficacy partial agonist with EC(50) = 12 nM and 45-fold selectivity over the adenosine A(3) receptor but lacking selectivity versus the A(1) and A(2A) subtypes. Compound 18, LUF5835, the 3-hydroxyphenyl analogue, is a full agonist with EC(50) = 10 nM.

1 FPL 67156 (6-N,N-diethyl-p,'y-dibromomethylene-D-ATP), is a newly synthesized analogue of ATP. 2 In a rabbit isolated tracheal epithelium preparation, measuring P2U-purinoceptor-dependent

Until now, more than 800 distinct G proteincoupled receptors (GPCRs) have been identified in the human genome. The four subtypes of the adenosine receptor (A 1 , A 2A , A 2B and A 3 receptor) belong to this large family of GPCRs that represent the most widely targeted pharmacological protein class. Since adenosine receptors are widespread throughout the body and involved in a variety of physiological processes and diseases, there is great interest in understanding how the different subtypes are regulated, as a basis for designing therapeutic drugs that either avoid or make use of this regulation. The major GPCR regulatory pathway involves phosphorylation of activated receptors by G protein-coupled receptor kinases (GRKs), a process that is followed by binding of arrestin proteins. This prevents receptors from activating downstream heterotrimeric G protein pathways, but at the same time allows activation of arrestin-dependent signalling pathways. Upon agonist treatment, adenosine receptor subtypes are differently regulated. For instance, the A 1 Rs are not (readily) phosphorylated and internalize slowly, showing a typical half-life of several hours, whereas the A 2A R and A 2B R undergo much faster downregulation, usually shorter than 1 h. The A 3 R is subject to even faster downregulation, often a matter of minutes. The fast desensitization of the A 3 R after agonist exposure may be therapeutically equivalent to antagonist occupancy of the receptor. This review describes the process of desensitization and internalization of the different adenosine subtypes in cell systems, tissues and in vivo studies. In addition, molecular mechanisms involved in adenosine receptor desensitization are discussed.