In vitroandin vivopharmacology of synthetic olivetol‐ or resorcinol‐derived cannabinoid receptor ligands

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Abstract
Background and purpose: We have previously reported the development of CB‐25 and CB‐52, two ligands of CB1and CB2cannabinoid receptors. We assessed here their functional activity.Experimental approach: The effect of the two compounds on forskolin‐induced cAMP formation in intact cells or GTP‐γ‐S binding to cell membranes, and their action on nociceptionin vivowas determined.Key results: CB‐25 enhanced forskolin‐induced cAMP formation in N18TG2 cells (EC50∼20 nM, max. stimulation=48%), behaving as an inverse CB1agonist, but it stimulated GTP‐γ‐S binding to mouse brain membranes, behaving as a partial CB1agonist (EC50=100 nM, max. stimulation=48%). At human CB1receptors, CB‐25 inhibited cAMP formation in hCB1‐CHO cells (EC50=1600 nM, max. inhibition=68% of CP‐55,940 effect). CB‐52 inhibited forskolin‐induced cAMP formation by N18TG2 cells (IC50=450 nM, max. inhibition=40%) and hCB1‐CHO cells (EC50=2600 nM, max. inhibition=62% of CP‐55,940 effect), and stimulated GTP‐γ‐S binding to mouse brain membranes (EC50=11 nM, max. stimulation∼16%). Both CB‐25 and CB‐52 showed no activity in all assays of CB2‐coupled functional activity and antagonized CP55940‐induced stimulation of GTP‐γ‐S binding to hCB2‐CHO cell membranes.In vivo, both compounds, administered i.p., produced dose‐dependent nociception in the plantar test carried out in healthy rats, and antagonised the anti‐nociceptive effect of i.p. WIN55,212‐2. In the formalin test in mice, however, the compounds counteracted both phases of formalin‐induced nociception.Conclusions and implications: CB‐25 and CB‐52 behavein vitromostly as CB1partial agonists and CB2neutral antagonists, whereas their activityin vivomight depend on the tonic activity of cannabinoid receptors.British Journal of Pharmacology(2006)149, 431–440. doi:10.1038/sj.bjp.0706888