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Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers.

AbstractBACKGROUND AND PURPOSE:
Racemic (R,S) AM1241 is a cannabinoid receptor 2 (CB(2))-selective aminoalkylindole with antinociceptive efficacy in animal pain models. The purpose of our studies was to provide a characterization of R,S-AM1241 and its resolved enantiomers in vitro and in vivo.
EXPERIMENTAL APPROACH:
Competition binding assays were performed using membranes from cell lines expressing recombinant human, rat, and mouse CB(2) receptors. Inhibition of cAMP was assayed using intact CB(2)-expressing cells. A mouse model of visceral pain (para-phenylquinone, PPQ) and a rat model of acute inflammatory pain (carrageenan) were employed to characterize the compounds in vivo.
KEY RESULTS:
In cAMP inhibition assays, R,S-AM1241 was found to be an agonist at human CB(2), but an inverse agonist at rat and mouse CB(2) receptors. R-AM1241 bound with more than 40-fold higher affinity than S-AM1241, to all three CB(2) receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB(2) receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. Antagonist blockade demonstrated that the in vivo effects of S-AM1241 were mediated by CB(2) receptors.
CONCLUSIONS AND IMPLICATIONS:
These findings constitute the first in vitro functional assessment of R,S-AM1241 at rodent CB(2) receptors and the first characterization of the AM1241 enantiomers in recombinant cell systems and in vivo. The greater antinociceptive efficacy of S-AM1241, the functional CB(2) agonist enantiomer of AM1241, is consistent with previous observations that CB(2) agonists are effective in relief of pain.
AuthorsB Bingham, P G Jones, A J Uveges, S Kotnis, P Lu, V A Smith, S-C Sun, L Resnick, M Chlenov, Y He, B W Strassle, T A Cummons, M J Piesla, J E Harrison, G T Whiteside, J D Kennedy
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 151 Issue 7 Pg. 1061-70 (Aug 2007) ISSN: 0007-1188 [Print] England
PMID17549048 (Publication Type: Journal Article)
Chemical References
  • AM 1241
  • Analgesics
  • Benzoxazines
  • Calcium Channel Blockers
  • Camphanes
  • Cannabinoids
  • Cyclohexanols
  • Indoles
  • Morpholines
  • Naphthalenes
  • Pyrazoles
  • Receptor, Cannabinoid, CB2
  • SR 144528
  • Tritium
  • Colforsin
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • Carrageenan
  • Cyclic AMP
  • iodopravadoline
Topics
  • Analgesics (pharmacology)
  • Animals
  • Benzoxazines (pharmacology)
  • CHO Cells
  • Calcium Channel Blockers (pharmacology)
  • Camphanes (pharmacology)
  • Cannabinoids (chemistry, metabolism, pharmacology)
  • Carrageenan (toxicity)
  • Colforsin (pharmacology)
  • Cricetinae
  • Cricetulus
  • Cyclic AMP (antagonists & inhibitors, metabolism)
  • Cyclohexanols (pharmacology)
  • Dose-Response Relationship, Drug
  • Humans
  • Hyperalgesia (chemically induced, physiopathology, prevention & control)
  • Indoles (pharmacology)
  • Mice
  • Morpholines (pharmacology)
  • Naphthalenes (pharmacology)
  • Protein Binding (drug effects)
  • Pyrazoles (pharmacology)
  • Radioligand Assay
  • Rats
  • Receptor, Cannabinoid, CB2 (agonists, genetics, metabolism)
  • Species Specificity
  • Stereoisomerism
  • Tritium

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