title: Adenosine A2A receptor antagonists: new 8-substituted 9-ethyladenines as tools for in vivo rat models of Parkinson's disease.
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.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino via S. Agostino 1, 62032 Camerino, MC, Italy. rosaria.volpini@unicam.it
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Ram Chandra
authors.initials: RC
authors.lastname: Mishra
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Ramadori
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Gloria
authors.initials: G
authors.lastname: Cristalli