Collect. Czech. Chem. Commun. 2011, 76, 1379-1393
Published online 2011-11-20 20:10:00

New 9-methyl-8-(4-hydroxyphenyl)adenine derivatives as A1 adenosine receptor antagonists

Catia Lambertuccia, Michela Buccionia, Barbara Cacciarib, Diego Dal Bena, Stephanie Federicoc, Karl-Norbert Klotzd, Gabriella Maruccia, Rosaria Volpinia, Giampiero Spallutoc and Gloria Cristallia,*

a School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy
b Dipartimento di Scienze Farmaceutiche, Università degli Studi di Ferrara, via Fossato di Mortara 17–19, 44100 Ferrara, Italy
c Dipartimento di Scienze Farmaceutiche, Università degli Studi di Trieste, Piazzale Europa 1, 34127 Trieste, Italy
d Institut für Pharmakologie und Toxikologie, Universität Würzburg, 97078 Würzburg, Germany


A new series of 9-methyladenines, bearing different bulky groups at the 8-position, were prepared and their affinity for the four human adenosine receptor subtypes were evaluated. All the synthesized compounds showed affinities at the A1, A2A, and A3AR subtypes ranging from nanomolar to micromolar levels with different degrees of A1 selectivity, while they resulted nearly inactive at A2BAR. In particular, 9-methyl-8-[4-(4-methylbenzyloxy)phenyl]- adenine showed A1AR affinity in the nanomolar range and good levels of selectivity versus the other receptor subtypes. Furthermore, a functional assay at mouse ileum allowed to assess the potency of selected compounds at A1AR subtype. Results showed that all the tested derivatives are neutral antagonists and their Kb values are in good agreement with the Ki values from radioligand binding assay at human A1AR, confirming that the effect is due to inhibition of this subtype.

Keywords: Adenosine receptors; Adenosine receptor antagonists; Adenine derivatives; A1AR functional studies; Receptors; Nucleobases; Heterocycles; Ligand design; Ligand effects.

References: 45 live references.