(a) Chemical structures and measured antagonist potencies for CB1 and CB2 receptors. (b) Crystal structure of CB2 receptor with AM10257 and predicted binding poses for hit compounds (c) 505, (d) 523, (e) 610, (f) 665, and (f) 673 in CB2 receptor, respectively. Key subpockets of the binding pocket marked as SP1, SP2, and SP3. (h-i) Concentration-response curves for the top antagonists in β-arrestin recruitment Tango assays at CB1
(h) and CB2
(i) receptors. The assays were carried out in the presence of 100 nM (EC80) of the dual CB1/CB2 agonist CP55,940. The compounds rimonabant (h) and SR144528 (i) served as positive controls. The data are presented as mean ± SEM from n=3 independent experiments, each run carried out in triplicate.