In the last few years, much effort has been directed towards the synthesis of selective adenosine receptor (AR) antagonists since they are attractive tools for pharmacological intervention in many pathophysiological conditions. During our studies aimed at obtaining new nonclassical adenosine antagonists devoid of phosphodiesterase (PDE) inhibition, a series of 2-pyridones and 2,5-quinolinediones (3a-f, 5a-f, 6a,c-f) has been synthesized as potential AR ligands. Binding affinities of the new compounds were determined for bovine and human adenosine A1, A2A, and A3 receptors. Compound 5f showed good affinity (Ki = 7.8 μM) towards human A1AR but no selectivity (Ki = 7.0 μM) towards human A2AAR, whereas compound 6f showed more affinity towards human A 2A (Ki = 16 μM) than A1 receptor (percentage inhibition at 10 μM concentration = 11). In the 1-100 μM range, the new compounds did not inhibit cardiac PDE3 activity at all. Molecular modeling studies carried out on 5f and 6f support the pharmacological results and suggest 6f as a potential lead compound selective towards A2AAR.
Quinolinedione nucleus as a novel scaffold for A1 and A 2A adenosine receptor antagonists
TRINCAVELLI, MARIA LETIZIA;
2008-01-01
Abstract
In the last few years, much effort has been directed towards the synthesis of selective adenosine receptor (AR) antagonists since they are attractive tools for pharmacological intervention in many pathophysiological conditions. During our studies aimed at obtaining new nonclassical adenosine antagonists devoid of phosphodiesterase (PDE) inhibition, a series of 2-pyridones and 2,5-quinolinediones (3a-f, 5a-f, 6a,c-f) has been synthesized as potential AR ligands. Binding affinities of the new compounds were determined for bovine and human adenosine A1, A2A, and A3 receptors. Compound 5f showed good affinity (Ki = 7.8 μM) towards human A1AR but no selectivity (Ki = 7.0 μM) towards human A2AAR, whereas compound 6f showed more affinity towards human A 2A (Ki = 16 μM) than A1 receptor (percentage inhibition at 10 μM concentration = 11). In the 1-100 μM range, the new compounds did not inhibit cardiac PDE3 activity at all. Molecular modeling studies carried out on 5f and 6f support the pharmacological results and suggest 6f as a potential lead compound selective towards A2AAR.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
