SR-144528, THE FIRST POTENT AND SELECTIVE ANTAGONIST OF THE CB2 CANNABINOID RECEPTOR

Based on both binding and functional data, this study introduces SR 14 4528 as the first, highly potent, selective and orally active antagoni st for the CB2 receptor. This compound which displays subnanomolar aff inity (K-i = 0.6 nM) for bath the rat spleen and cloned human CB2 rece ptors has a 700-fold lower affinity (K-i = 400 nM) for both the rat br ain and cloned human CB1 receptors. Furthermore it shows no affinity f or any of the more than 70 receptors, ion channels or enzymes investig ated (IC50 > 10 mu M). In vitro, SR 144528 antagonizes the inhibitory effects of the cannabinoid receptor agonist CP 55,940 on forskolin-sti mulated adenylyl cyclase activity in cell lines permanently expressing the h CB2 receptor (EC50 = 10 nM) but not in cells expressing the h C B1 (no effect at 10 mu M). Furthermore, SR 144528 is able to selective ly block the mitogen-activated protein kinase activity induced by CP 5 5,940 in cell lines expressing h CB2 (IC50 = 39 nM) whereas in cells e xpressing h CB1 an IC50 value of more than 1 mu M is found. In additio n, SR 144528 is shown to antagonize the stimulating effects of CP 55,9 40 on human tonsillar B-cell activation evoked by crosslinking of surf ace Igs (IC50 = 20 nM). In vivo, after oral administration SR 144528 t otally displaced the ex vivo [H-3]-CP 55,940 binding to mouse spleen m embranes (ED50 = 0.35 mg/kg) with a long duration of action. In contra st, after the oral route it does not interact with the cannabinoid rec eptor expressed in the mouse brain (CB1). It is expected that SR 14452 8 will provide a powerful tool to investigate the in vivo functions of the cannabinoid system in the immune response.