1860-7187/asset/2452_left.gif?v=1&s=4110e7425ac5e40773dfb0778cfefa62f1594507)
1860-7187/asset/2452_right.gif?v=1&s=8458ea1f15af84217b579501ed7d7733bef04a94)
Full Paper
Adenosine A2A Receptor Antagonists: New 8-Substituted 9-Ethyladenines as Tools for in vivo Rat Models of Parkinson's Disease
Article first published online: 2 APR 2009
DOI: 10.1002/cmdc.200800434
Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Issue
ChemMedChem
Special Issue: XIX NMMC Verona 2008
Volume 4, Issue 6, pages 1010–1019, June 8, 2009
Additional Information
How to Cite
Volpini, R., Dal Ben, D., Lambertucci, C., Marucci, G., Mishra, R., Ramadori, A., Klotz, K.-N., Trincavelli, M., Martini, C. and Cristalli, G. (2009), Adenosine A2A Receptor Antagonists: New 8-Substituted 9-Ethyladenines as Tools for in vivo Rat Models of Parkinson's Disease. ChemMedChem, 4: 1010–1019. doi: 10.1002/cmdc.200800434
Publication History
- Issue published online: 28 MAY 2009
- Article first published online: 2 APR 2009
- Manuscript Revised: 20 FEB 2009
- Manuscript Received: 15 DEC 2008
Funded by
- Italian Ministry for University and Research. Grant Numbers: PRIN2006, FIRB RBN503YA3L project
- Abstract
- Article
- References
- Cited By
Keywords:
- adenosine;
- antagonists;
- molecular modeling;
- purine derivatives;
- receptors
Graphical 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 AA2AR.
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 AA2AR.
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.