In vitro and in vivo pharmacology of synthetic olivetol- or resorcinol-derived cannabinoid receptor ligands

M. G. Cascio, T. Bisogno, E. Palazzo, A. Thomas, M. Van Der Stelt, A. Brizzi, V. De Novellis, I. Marabese, R. Ross, T. Van De Doelen, V. Brizzi, R. Pertwee, S. Maione, V. Di Marzo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)431-440
Number of pages10
JournalBritish Journal of Pharmacology
Issue number4
Publication statusPublished - 11 Oct 2006
Externally publishedYes


  • Agonist
  • Antagonist
  • Endocannabinoid
  • Inverse agonist
  • Pain
  • Partial agonist
  • Receptor


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