Abstract | BACKGROUND 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.
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Authors | B 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 |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 151
Issue 7
Pg. 1061-70
(Aug 2007)
ISSN: 0007-1188 [Print] England |
PMID | 17549048
(Publication Type: Journal Article)
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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
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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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