Zusammenfassung
A number of 2-substituted 5'-N-ethylcarboxamidoadenosine (NECA) derivatives
was investigated for their affinity and selectivity at human A3 adenosine
receptors. The compounds were tested in radioligand competition studies
and modulation of adenylyl cyclase activity on membranes from CHO
cell lines stably transfected with the four human adenosine receptor
subtypes. In binding studies the most potent compound, 2-(3-hydroxy-3-phenyl)propyn-1-yl-NECA
(PHPNECA), exhibited a subnanomolar affinity for A3 adenosine receptors
with a Ki value of 0.4 nM. As opposed to the limited A3 selectivity
of PHPNECA, a 100-fold selectivity compared to both A1 and A2A receptors
was found for 2-(2-phenyl)ethynyl-NECA (PENECA; Ki 6 nM). The EC50
values for activation of adenylyl cyclase via A2A adenosine receptors
were in good agreement with the respective Ki values from binding
experiments. In contrast, IC50 values for A1 and A3 receptor-mediated
inhibition of adenylyl cyclase were shifted to higher values compared
to the respective affinities determined in radioligand competition
studies. Similar discrepancies between binding and functional data
have been observed for the inhibitory A1 adenosine receptor in previous
studies. Therefore, the same A3 selectivity of PENECA compared to
A1 receptors was found in binding and adenylyl cyclase inhibition
whereas the selectivity compared to A2A receptors that was detected
in ligand binding was obscured in the functional assay. The series
of compounds presented in this study identifies 2-substitution of
the purine system as a promising target for the development of A3-selective
high-affinity ligands.
Nutzer