Adenosine A2A receptor antagonists: new 8-substituted 9-ethyladenines
as tools for in vivo rat models of Parkinson's disease
ChemMedChem, 4 (6):
1010-9 (June 2009)Volpini, Rosaria Dal Ben, Diego Lambertucci, Catia Marucci, Gabriella
Mishra, Ram Chandra Ramadori, Anna Teresa Klotz, Karl-Norbert Trincavelli,
Maria Letizia Martini, Claudia Cristalli, Gloria Research Support,
Non-U.S. Gov't Germany ChemMedChem ChemMedChem. 2009 Jun;4(6):1010-9..Abstract
A new series of 8-substituted 9-ethyladenine derivatives has been
synthesized and tested at rat and human adenosine receptors. Binding
data demonstrates that some compounds could represent new tools suitable
for in vivo studies in rat models of Parkinson's disease and for
the design of new molecules with improved affinity and selectivity
at human AA(2A)R.Clinical evidence has demonstrated that AA(2A)R
antagonists could be an alternative approach to the treatment of
Parkinson's disease. Recently, three 9-ethyladenine derivatives bearing
a bromine atom, an ethoxy group, and a furyl ring, respectively,
in the 8-position have been reported to ameliorate motor deficits
in rat Parkinson's disease models, suggesting a potential therapeutic
role for these compounds. Starting from these observations, a new
series of 9-ethyladenine derivatives, bearing different substituents
such as halogens, alkoxy groups, aromatic and heteroaromatic rings
in the 8-position, were synthesized. Radioligand binding assays demonstrated
that some of the new compounds bind rat AA(2A)R with higher affinity
than the previously reported congeners and that there is a good correlation
between binding to rat and human receptors. Hence, the new molecules
could represent new tools suitable for the in vivo studies in rat
models of Parkinson's disease. Finally, a molecular docking analysis
of the compounds was performed using a homology model of rat AA(2A)R,
built using the human crystal structure as the template, and results
are in agreement with the binding data.