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Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers.
Br J Pharmacol 2007; 151(7):1061-70BJ

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.

Authors+Show Affiliations

Neuroscience Discovery Research, Wyeth Research, Princeton, NJ 08543, USA. binghab@wyeth.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17549048

Citation

Bingham, B, et al. "Species-specific in Vitro Pharmacological Effects of the Cannabinoid Receptor 2 (CB2) Selective Ligand AM1241 and Its Resolved Enantiomers." British Journal of Pharmacology, vol. 151, no. 7, 2007, pp. 1061-70.
Bingham B, Jones PG, Uveges AJ, et al. Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers. Br J Pharmacol. 2007;151(7):1061-70.
Bingham, B., Jones, P. G., Uveges, A. J., Kotnis, S., Lu, P., Smith, V. A., ... Kennedy, J. D. (2007). Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers. British Journal of Pharmacology, 151(7), pp. 1061-70.
Bingham B, et al. Species-specific in Vitro Pharmacological Effects of the Cannabinoid Receptor 2 (CB2) Selective Ligand AM1241 and Its Resolved Enantiomers. Br J Pharmacol. 2007;151(7):1061-70. PubMed PMID: 17549048.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers. AU - Bingham,B, AU - Jones,P G, AU - Uveges,A J, AU - Kotnis,S, AU - Lu,P, AU - Smith,V A, AU - Sun,S-C, AU - Resnick,L, AU - Chlenov,M, AU - He,Y, AU - Strassle,B W, AU - Cummons,T A, AU - Piesla,M J, AU - Harrison,J E, AU - Whiteside,G T, AU - Kennedy,J D, Y1 - 2007/06/04/ PY - 2007/6/6/pubmed PY - 2007/11/6/medline PY - 2007/6/6/entrez SP - 1061 EP - 70 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 151 IS - 7 N2 - 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. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/17549048/Species_specific_in_vitro_pharmacological_effects_of_the_cannabinoid_receptor_2__CB2__selective_ligand_AM1241_and_its_resolved_enantiomers_ L2 - https://doi.org/10.1038/sj.bjp.0707303 DB - PRIME DP - Unbound Medicine ER -