Adenosine is an abundant metabolite which is closely linked to maintaining the energy balance of our body. It is the molecule that makes us fall asleep if we stay up for too long and it is the action of adenosine that is blocked by our attempts to stay awake with caffeine. Adenosine is a regulator of numerous cell functions in pretty much every organ or cell and its actions are mediated via four subtypes of G protein-coupled receptors. The A1 and A3 subtypes mediate an inhibition of adenylyl cyclase and in addition they may stimulate a Ca2+ signal and open K+ channels. The A2A and A2B subtypes are coupled to adenylyl cyclase via Gs and their stimulation causes a rise in intracellular cAMP. Due to their widespread distribution adenosine receptors are candidate targets for the treatment of many diseases including asthma, ischemic conditions, Parkinson’s and other CNS diseases. Recent results also show a potential in the treatment of certain tumors. For review see Fredholm et al. 2001, Pharmacol. Rev. 53:1-26.
Ligands for adenosine receptor subtypes
Although numerous agonists and antagonists for adenosine receptors have been developed over the past two decades there is still a need for more potent and selective compounds which specifically activate or block individual receptor subtypes. In collaborations with several groups of medicinal chemists we are developing and characterizing new molecules with improved affinity and selectivity. Recently, we have introduced a series of compounds with high selectivity and nanomolar affinity for A3 adenosine receptors (Volpini et al. 2002). Based on one of these compounds (HEMADO) a tritiated radioligand was recently developed which is now commercially available from Biotrend, Köln, Germany.
Adenosine receptor modeling
In particular the A3 adenosine receptor subtype is characterized by a marked species difference in antagonist binding between the human and the rat receptor. Such differences may help to understand the ligand-receptor interaction in more detail. Based on predictions from receptor modeling and ligand docking studies (Stefano Moro, Padova, Italy) we are generating receptor mutants with altered pharmacological characteristics. It is attempted to assign species-specific characteristics to single amino acid side chains.
Adenosine receptors in cancer cells
Adenosine receptors have been found on many tumor cells and there is evidence that these receptors may serve as targets for pharmacological control of tumor growth and development. We have recently started to identify adenosine receptor subtypes in different breast cancer cell lines and found a cell line that exclusively expresses high levels of A2B adenosine receptors. The A2B receptors in these estrogen receptor-negative MDA cells are coupled to adenylyl cyclase via the stimulatory G protein Gs.In addition, they cause a PLC-dependent increase in intracellular Ca2+ levels, presumably via the Gq/11 pathway. This adenosine-mediated Ca2+ signal may be an interesting target for anti-cancer treatment. Currently, we are studying A2B-mediated MAP kinase signaling which might also be of importance for an effect of adenosine on the regulation of growth and proliferation. In addition to breast cancer cells we are investigating the presence of adenosine receptor subtypes on various tumor cells including melanoma, ovarian and endometrial tumors.
Sonja Kachler (lab technician)
Marthe Koussemou (biologist)