Artikel,
Molecular modelling study of 2-phenylethynyladenosine (PEAdo) derivatives as highly selective A(3) adenosine receptor ligands
Purinergic Signal, 2 (4): 589-94 (November 2006)Dal Ben, Diego Lambertucci, Catia Taffi, Sara Vittori, Sauro Volpini, Rosaria Cristalli, Gloria Klotz, Karl-Norbert Netherlands Purinergic signalling Purinergic Signal. 2006 Nov;2(4):589-94. Epub 2006 Aug 10..
Zusammenfassung
A series of 2-phenylethynyladenosine (PEAdo) derivatives substituted
in the N(6)- and 4'-position was synthesised and the new derivatives
were tested at the four human adenosine receptors stably transfected
into Chinese hamster ovary (CHO) cells, using radioligand binding
studies (A(1), A(2A), A(3)) or adenylyl cyclase activity assay (A(2B)).
Binding studies showed that the presence of a phenyl ethynyl group
in the 2 position of adenosine favoured the interaction with A(3)
receptors, resulting in compounds endowed with high affinity and
selectivity for the A(3) subtype. Additional substitution of the
N(6)- and 4'-position increases both A(3) affinity and selectivity.
The results showed that the new compounds have a good affinity for
the A(3) receptor and in particular, the N(6)-methoxy-2-phenylethynyl-5'-N-methylcarboxamidoadenosine,
with a K(i) at A(3) of 1.9 nM and a selectivity A(1)/A(3) and A(2A)/A(3)
of 4,800- and 8,600-fold, respectively. Therefore, it is one of the
most potent and selective agonists at the human A(3) adenosine receptor
subtype reported so far. Furthermore, functional assays of inhibition
of 10 muM forskolin-stimulated cAMP production via the adenosine
A(3) receptor revealed that the new trisubstituted adenosine derivatives
behave as full agonist of this receptor subtype. Docking analysis
of these compounds was performed at a homology model of the human
A(3) receptor based on the bovine rhodopsin crystal structure as
template, and the results are in accordance with the biological data.
