1. Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers.
- Author
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Bingham, B., Jones, P. G., Uveges, A. J., Kotnis, S., Lu, P., Smith, V. A., Sun, S.-C., Resnick, L., Chlenov, M., He, Y., Strassle, B. W., Cummons, T. A., Piesla, M. J., Harrison, J. E., Whiteside, G. T., and Kennedy, J. D.
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CANNABINOIDS , *CELL lines , *ENANTIOMERS , *IMMUNE system , *LABORATORY mice , *ANIMAL models in research , *HYDROCARBON metabolism , *CALCIUM antagonists , *ALCOHOLS (Chemical class) , *ANALGESICS , *ANIMAL experimentation , *CELL receptors , *CHEMISTRY , *CYCLIC adenylic acid , *DOSE-effect relationship in pharmacology , *HAMSTERS , *HETEROCYCLIC compounds , *HYDROCARBONS , *HYPERALGESIA , *IMMUNITY , *MICE , *POLYSACCHARIDES , *RADIOISOTOPES in medical diagnosis , *RATS , *RODENTS , *TERPENES , *INDOLE compounds , *CHEMICAL inhibitors , *PHARMACODYNAMICS , *PREVENTION - 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. [ABSTRACT FROM AUTHOR]- Published
- 2007
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