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

M. G. Cascio, T. Bisogno, E. Palazzo, Alan Donald Thomas, M. van der Stelt, A. Brizzi, V. De Novellis, I. Marabese, Ruth Alexandra Ross, T. van de Doelen, V. Brizzi, Roger Guy Pertwee, S. Maione, V. Di Marzo

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background and purpose: We have previously reported the development of CB-25 and CB-52, two ligands of CB1 and CB2 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-gamma-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 (EC50 similar to 20 nM, max. stimulation = 48%), behaving as an inverse CB1 agonist, but it stimulated GTP-gamma-S binding to mouse brain membranes, behaving as a partial CB1 agonist (EC50 = 100 nM, max. stimulation = 48%). At human CB1 receptors, CB-25 inhibited cAMP formation in hCB(1)-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 hCB(1)-CHO cells (EC50 = 2600 nM, max. inhibition = 62% of CP-55,940 effect), and stimulated GTP-gamma-S binding to mouse brain membranes (EC50 = 11 nM, max. stimulation similar to 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-gamma-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 CB1 partial agonists and CB2 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
Volume149
Issue number4
DOIs
Publication statusPublished - Oct 2006

Keywords

  • agonist
  • antagonist
  • inverse agonist
  • partial agonist
  • receptor
  • endocannabinoid
  • pain
  • acid amide hydrolase
  • CB2 receptor
  • anandamide
  • neurons
  • cells
  • rat
  • 2-arachidonoylglycerol
  • hyperalgesia

Cite this

Cascio, M. G., Bisogno, T., Palazzo, E., Thomas, A. D., van der Stelt, M., Brizzi, A., ... Di Marzo, V. (2006). In vitro and in vivo pharmacology of synthetic olivetol- or resorcinol-derived cannabinoid receptor ligands. British Journal of Pharmacology, 149(4), 431-440. https://doi.org/10.1038/sj.bjp.0706888

In vitro and in vivo pharmacology of synthetic olivetol- or resorcinol-derived cannabinoid receptor ligands. / Cascio, M. G.; Bisogno, T.; Palazzo, E.; Thomas, Alan Donald; van der Stelt, M.; Brizzi, A.; De Novellis, V.; Marabese, I.; Ross, Ruth Alexandra; van de Doelen, T.; Brizzi, V.; Pertwee, Roger Guy; Maione, S.; Di Marzo, V.

In: British Journal of Pharmacology, Vol. 149, No. 4, 10.2006, p. 431-440.

Research output: Contribution to journalArticle

Cascio, MG, Bisogno, T, Palazzo, E, Thomas, AD, van der Stelt, M, Brizzi, A, De Novellis, V, Marabese, I, Ross, RA, van de Doelen, T, Brizzi, V, Pertwee, RG, Maione, S & Di Marzo, V 2006, 'In vitro and in vivo pharmacology of synthetic olivetol- or resorcinol-derived cannabinoid receptor ligands', British Journal of Pharmacology, vol. 149, no. 4, pp. 431-440. https://doi.org/10.1038/sj.bjp.0706888
Cascio, M. G. ; Bisogno, T. ; Palazzo, E. ; Thomas, Alan Donald ; van der Stelt, M. ; Brizzi, A. ; De Novellis, V. ; Marabese, I. ; Ross, Ruth Alexandra ; van de Doelen, T. ; Brizzi, V. ; Pertwee, Roger Guy ; Maione, S. ; Di Marzo, V. / In vitro and in vivo pharmacology of synthetic olivetol- or resorcinol-derived cannabinoid receptor ligands. In: British Journal of Pharmacology. 2006 ; Vol. 149, No. 4. pp. 431-440.
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abstract = "Background and purpose: We have previously reported the development of CB-25 and CB-52, two ligands of CB1 and CB2 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-gamma-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 (EC50 similar to 20 nM, max. stimulation = 48{\%}), behaving as an inverse CB1 agonist, but it stimulated GTP-gamma-S binding to mouse brain membranes, behaving as a partial CB1 agonist (EC50 = 100 nM, max. stimulation = 48{\%}). At human CB1 receptors, CB-25 inhibited cAMP formation in hCB(1)-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 hCB(1)-CHO cells (EC50 = 2600 nM, max. inhibition = 62{\%} of CP-55,940 effect), and stimulated GTP-gamma-S binding to mouse brain membranes (EC50 = 11 nM, max. stimulation similar to 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-gamma-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 CB1 partial agonists and CB2 neutral antagonists, whereas their activity in vivo might depend on the tonic activity of cannabinoid receptors.",
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T1 - In vitro and in vivo pharmacology of synthetic olivetol- or resorcinol-derived cannabinoid receptor ligands

AU - Cascio, M. G.

AU - Bisogno, T.

AU - Palazzo, E.

AU - Thomas, Alan Donald

AU - van der Stelt, M.

AU - Brizzi, A.

AU - De Novellis, V.

AU - Marabese, I.

AU - Ross, Ruth Alexandra

AU - van de Doelen, T.

AU - Brizzi, V.

AU - Pertwee, Roger Guy

AU - Maione, S.

AU - Di Marzo, V.

PY - 2006/10

Y1 - 2006/10

N2 - Background and purpose: We have previously reported the development of CB-25 and CB-52, two ligands of CB1 and CB2 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-gamma-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 (EC50 similar to 20 nM, max. stimulation = 48%), behaving as an inverse CB1 agonist, but it stimulated GTP-gamma-S binding to mouse brain membranes, behaving as a partial CB1 agonist (EC50 = 100 nM, max. stimulation = 48%). At human CB1 receptors, CB-25 inhibited cAMP formation in hCB(1)-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 hCB(1)-CHO cells (EC50 = 2600 nM, max. inhibition = 62% of CP-55,940 effect), and stimulated GTP-gamma-S binding to mouse brain membranes (EC50 = 11 nM, max. stimulation similar to 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-gamma-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 CB1 partial agonists and CB2 neutral antagonists, whereas their activity in vivo might depend on the tonic activity of cannabinoid receptors.

AB - Background and purpose: We have previously reported the development of CB-25 and CB-52, two ligands of CB1 and CB2 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-gamma-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 (EC50 similar to 20 nM, max. stimulation = 48%), behaving as an inverse CB1 agonist, but it stimulated GTP-gamma-S binding to mouse brain membranes, behaving as a partial CB1 agonist (EC50 = 100 nM, max. stimulation = 48%). At human CB1 receptors, CB-25 inhibited cAMP formation in hCB(1)-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 hCB(1)-CHO cells (EC50 = 2600 nM, max. inhibition = 62% of CP-55,940 effect), and stimulated GTP-gamma-S binding to mouse brain membranes (EC50 = 11 nM, max. stimulation similar to 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-gamma-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 CB1 partial agonists and CB2 neutral antagonists, whereas their activity in vivo might depend on the tonic activity of cannabinoid receptors.

KW - agonist

KW - antagonist

KW - inverse agonist

KW - partial agonist

KW - receptor

KW - endocannabinoid

KW - pain

KW - acid amide hydrolase

KW - CB2 receptor

KW - anandamide

KW - neurons

KW - cells

KW - rat

KW - 2-arachidonoylglycerol

KW - hyperalgesia

U2 - 10.1038/sj.bjp.0706888

DO - 10.1038/sj.bjp.0706888

M3 - Article

VL - 149

SP - 431

EP - 440

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 4

ER -