Functional selectivity of adenosine A1 receptor ligands?
The concept of functional selectivity offers great potential for the development of drugs that selectively activate a specific intracellular signaling pathway. During the last few years, it has become possible to systematically analyse compound libraries on G protein-coupled receptors (GPCRs) for this 'biased' form of signaling. We screened over 800 compounds targeting the class of adenosine A(1) receptors using a β-arrestin-mediated signaling assay in U2OS cells as a G protein-independent readout for GPCR activation. A selection of compounds was further analysed in a G protein-mediated GTPγS assay. Additionally, receptor affinity of these compounds was determined in a radioligand binding assay with the agonist [(3)H]CCPA. Of all compounds tested, only LUF5589 9 might be considered as functionally selective for the G protein-dependent pathway, particularly in view of a likely overestimation of β-arrestin signaling in the U2OS cells. Altogether, our study shows that functionally selective ligands for the adenosine A(1) receptor are rare, if existing at all. A thorough analysis of biased signaling on other GPCRs also reveals that only very few compounds can be considered functionally selective. This might indicate that the concept of functional selectivity is less common than speculated.
Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300 RA, Leiden, The Netherlands.
Ellen V
EV
Langemeijer
Dennis
D
Verzijl
Stefan J
SJ
Dekker
Ad P
AP
Ijzerman
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D019393:Arrestin / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003627:Data Interpretation, Statistical; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008024:Ligands; D011869:Radioligand Assay; D043682:Receptor, Adenosine A1 / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D019393:Arrestin; D008024:Ligands; D043682:Receptor, Adenosine A1; D043562:Receptors, G-Protein-Coupled; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C058394:2-chloro-N(6)cyclopentyladenosine; D000241:Adenosine