2- and 8-alkynyl-9-ethyladenines: Synthesis and biological activity
at human and rat adenosine receptors
Purinergic Signal, 1 (2):
173-81 (June 2005)Volpini, Rosaria Costanzi, Stefano Lambertucci, Catia Vittori, Sauro
Martini, Claudia Trincavelli, M Letizia Klotz, Karl-Norbert Cristalli,
Gloria Netherlands Purinergic signalling Purinergic Signal. 2005
Jun;1(2):173-81. Epub 2005 Mar 17..Abstract
The synthesis of a series of 9-ethyladenine derivatives bearing alkynyl
chains in 2- or 8-position was undertaken, based on the observation
that replacement of the sugar moiety in adenosine derivatives with
alkyl groups led to adenosine receptor antagonists. All the synthesized
compounds were tested for their affinity at human and rat A(1), A(2A),
and A(3) adenosine receptors in binding assays; the activity at the
human A(2B) receptor was determined in adenylyl cyclase experiments.
Biological data showed that the 2-alkynyl derivatives possess good
affinity and are slightly selective for the human A(2A) receptor.
The same compounds tested on the rat A(1) and A(2A) subtypes showed
in general lower affinity for both receptors. On the other hand,
the affinity of the 8-alkynyl derivatives at the human A(1), A(2A),
and A(2B) receptors proved to be lower than that of the corresponding
2-alkynyl derivatives. On the contrary, the affinity of the same
compounds for the human A(3) receptor was improved, resulting in
A(3) selectivity. As in the case of the 2-alkynyl-substituted compounds,
the 8-alkynyl derivatives showed decreased affinity for rat receptors.
However, it is worthwhile to note that the 8-phenylethynyl-9-ethyladenine
was the most active compound of the two series (K (i) in the nanomolar
range) at both the human and rat A(3) subtype. Docking experiments
of the 2- and 8-phenylethynyl-9-ethyladenines, at a rhodopsin-based
homology model, gave a rational explanation of the preference of
the human A(3) receptor for the 8-substituted compound.