Clinical evidence has demonstrated that AA2AR 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 AA2AR 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 AA2AR, built using the human crystal structure as the template, and results are in agreement with the binding data.
Adenosine A(2A) receptor antagonists: new 8-substituted 9-ethyladenines as tools for in vivo rat models of Parkinson's disease
VOLPINI, Rosaria;DAL BEN, DIEGO;LAMBERTUCCI, Catia;MARUCCI, Gabriella;CRISTALLI, Gloria
2009-01-01
Abstract
Clinical evidence has demonstrated that AA2AR 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 AA2AR 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 AA2AR, built using the human crystal structure as the template, and results are in agreement with the binding data.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
