QSAR analysis of 2-alkyloxy and 2-aralkyloxy adenosine A 1- and A 2-agonists

Abstract

A quantitative structure-activity relationship (QSAR) analysis of a series 2-alkyloxy-, 2-aryloxy- and 2-aralkyloxy-adenosines has been performed. Various theoretical 3-D electronic and topological descriptors encoding their molecular structure were estimated and the structure-activity correlations were evaluated. A cluster analysis of the affinity constants of the compounds was carried out, and according to the obtained results the QSAR analysis was developed at two levels. The results of this investigation allowed a distinction to be made between A1- and A2-receptor selectivity of the compounds due to structural reasons. It was shown that small and less lipophilic substituents may enhance the A1-receptor selectivity of the compounds. Hydrophobic and bulky cycloalkyl substituents greatly enhance A2-receptor selectivity. The more lipophilic and rigid aromatic substituents increase the affinity, but decrease selectivity at both receptors. Adenosine agonist activity is also determined by the electron-donating properties of the purine ring and of certain atoms in this aromatic system: the N6 atom in A1-selective ligands and the N1, N7, C2, C5, C6, C8 atoms in A2-selecti ve ligands appear to constitute part of the pharrnacophore of the molecules.