The article titled above has been published in the Journal CHEMMEDCHEM.

ChemMedChem

ChemMedChem

Volume 4 Issue 6, Pages 1010 - 1019

Special Issue: XIX NMMC Verona 2008

Published Online: 2 Apr 2009

Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA

Full Paper

Adenosine A2A Receptor Antagonists: New 8-Substituted 9-Ethyladenines as Tools for in vivo Rat Models of Parkinson’s Disease
Rosaria Volpini, Prof. 1 *, Diego Dal Ben, Dr. 1, Catia Lambertucci, Dr. 1, Gabriella Marucci, Prof. Dr. 1, Ram Chandra Mishra, Dr. 1, Anna Teresa Ramadori, Dr. 1, Karl-Norbert Klotz, Prof. 2, Maria Letizia Trincavelli, Dr. 3, Claudia Martini, Prof. 3, Gloria Cristalli, Prof. 1
1Dipartimento di Scienze Chimiche, Università di Camerino via S. Agostino 1, 62032 Camerino (MC) (Italy), Fax: (+39) 0737-402295
2Institut für Pharmakologie und Toxikologie, Versbacher Str. 9, 97078 Würzburg (Germany)
3Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Via Bonanno Pisano 6, 56010 Pisa (Italy)
email: Rosaria Volpini (rosaria.volpini@unicam.it)

*Correspondence to Rosaria Volpini, 1Dipartimento di Scienze Chimiche, Università di Camerino via S. Agostino 1, 62032 Camerino (MC) (Italy), Fax: (+39) 0737-402295

Funded by:
Italian Ministry for University and Research; Grant Number: PRIN2006, FIRB RBN503YA3L project

Keywords
adenosine • antagonists • molecular modeling • purine derivatives • receptors
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.
Received: 15 December 2008; Revised: 20 February 2009

Digital Object Identifier (DOI)

10.1002/cmdc.200800434  About DOI

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