A number of N6-(N-arylcarbamoyl)-2-substituted-9-benzyl-8-azaadenines, obtained by a modification of the synthetic scheme used to prepare selective A1 ligands, by only three or two steps, are described. At first we prepared a series of 2-phenyl-9-benzyl-8-azaadenines having as N6 substituent a variously substituted N-phenylcarbamoyl group. Some of these derivatives demonstrated good affinity towards the A3 subtype but low selectivity. Compounds having p-CF3, p-F and p-OCH3, as substituents on the phenylcarbamoyl group were selected as lead compounds for the second part of this study. Without modifying the N6 substituent, which would assure A3 affinity, we varied the 9 and 2 positions on these molecules to enhance selectivity. Some compounds having a p-methyl group on the 2-phenyl substituent showed a very good affinity and selectivity for the A3 subtype, revealing the first class of A3 adenosine receptor selective antagonists with a bicyclic structure strictly correlated to the adenine nucleus. The molecular modelling work, carried out using the DOCK program, supplied two models which may be useful for a better understanding of the binding modes. Both models highlighted the preferred interacting tautomeric forms of the antagonists for human A1 and A3 receptors.
|Autori:||G. BIAGI; A. M. BIANUCCI; A. COI; B. COSTA; L. FABBRINI; GIORGI I; O. LIVI; I. MICCO; F. PACCHINI; E. SANTINI; M. LEONARDI; F. AHMAD NOFAL; O. LEROY SALERNI; V. SCARTONI|
|Titolo:||2,9-Disubstituted-N6-(arylcarbamoyl)-8-azaadenines as new selective A3 adenosine receptor antagonists: Synthesis, biochemical and molecular modelling studies|
|Anno del prodotto:||2005|
|Appare nelle tipologie:||1.1 Articolo in rivista|