Document Detail

Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers.
MedLine Citation:
PMID:  17549048     Owner:  NLM     Status:  MEDLINE    
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.
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
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Publication Detail:
Type:  Journal Article     Date:  2007-06-04
Journal Detail:
Title:  British journal of pharmacology     Volume:  151     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2007 Aug 
Date Detail:
Created Date:  2007-07-30     Completed Date:  2007-11-02     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1061-70     Citation Subset:  IM    
Neuroscience Discovery Research, Wyeth Research, Princeton, NJ 08543, USA.
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MeSH Terms
Analgesics / pharmacology
Benzoxazines / pharmacology
Bornanes / pharmacology
CHO Cells
Calcium Channel Blockers / pharmacology
Cannabinoids / chemistry,  metabolism,  pharmacology
Carrageenan / toxicity
Cyclic AMP / antagonists & inhibitors,  metabolism
Cyclohexanols / pharmacology
Dose-Response Relationship, Drug
Forskolin / pharmacology
Hyperalgesia / chemically induced,  physiopathology,  prevention & control
Indoles / pharmacology
Morpholines / pharmacology
Naphthalenes / pharmacology
Protein Binding / drug effects
Pyrazoles / pharmacology
Radioligand Assay
Receptor, Cannabinoid, CB2 / agonists*,  genetics,  metabolism
Species Specificity
Reg. No./Substance:
0/AM 1241; 0/Analgesics; 0/Benzoxazines; 0/Bornanes; 0/Calcium Channel Blockers; 0/Cannabinoids; 0/Cyclohexanols; 0/Indoles; 0/Morpholines; 0/Naphthalenes; 0/Pyrazoles; 0/Receptor, Cannabinoid, CB2; 0/SR 144528; 0/iodopravadoline; 10028-17-8/Tritium; 134959-51-6/Win 55212-2; 60-92-4/Cyclic AMP; 66428-89-5/Forskolin; 83003-12-7/3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; 9000-07-1/Carrageenan
Erratum In:
Br J Pharmacol. 2007 Aug;151(7):1137

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