Background and purpose: We have previously reported the development of CB-25 and CB-52, two ligands of CB 1 and CB 2 cannabinoid 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 nociception in vivo was determined. Key results: CB-25 enhanced forskolin-induced cAMP formation in N18TG2 cells (EC 50 ∼ 20 nM, max. stimulation = 48%), behaving as an inverse CB 1 agonist, but it stimulated GTP-γ-S binding to mouse brain membranes, behaving as a partial CB 1 agonist (EC 50 = 100 nM, max. stimulation = 48%). At human CB 1 receptors, CB-25 inhibited cAMP formation in hCB 1-CHO cells (EC 50 =1600 nM, max. inhibition = 68% of CP-55,940 effect). CB-52 inhibited forskolin-induced cAMP formation by N18TG2 cells (IC 50 = 450 nM, max. inhibition = 40%) and hCB 1-CHO cells (EC 50 = 2600 nM, max. inhibition 62% of CP-55,940 effect), and stimulated GTP-γ-S binding to mouse brain membranes (EC 50 = 11 nM, max. stimulation ∼ 16%). Both CB-25 and CB-52 showed no activity in all assays of CB 2-coupled functional activity and antagonized CP55940-induced stimulation of GTP-γ-S binding to hCB 2-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 behave in vitro mostly as CB 1 partial agonists and CB 2 neutral antagonists, whereas their activity in vivo might depend on the tonic activity of cannabinoid receptors.
- Inverse agonist
- Partial agonist