Pharmacological evaluation of a novel cannabinoid 2 (CB2) ligand, PF-03550096, in vitro and in vivo by using a rat model of visceral hypersensitivity.

Abstract

Previous studies have shown that cannabinoid 2 (CB(2))-receptor agonists might have analgesic effects on visceral hypersensitivity. To extend these results, we have determined the pharmacological characteristics of a newly designed CB(2) ligand, N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (PF-03550096), in vitro and in vivo. PF-03550096 showed high affinity to human (K(i) = 7.9 +/- 1.7 nM) and rat CB(2) receptors (K(i) = 47 +/- 5.6 nM). In a cell-based functional assay, PF-03550096 behaved as a full agonist and showed high selectivity for human CB(2) receptors. Orally administered PF-03550096 (3, 10 mg/kg) inhibited the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced decrease in colonic pain threshold with statistical significance. The inhibitory effect of PF-03550096 (10 mg/kg) was significantly reversed by a selective CB(2) antagonist, N-(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl-5-(4-chloro-3-methylphenyl)-1(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), while SR144528 itself did not modify colonic pain threshold. These results indicate that PF-03550096 is a potent CB(2) agonist and possesses efficacy in a rat model of visceral hypersensitivity.

• Authors: Akira Kikuchi, Katsuyo Ohashi, Yutaka Sugie, Hiromi Sugimoto, Hirofumi Omura
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 106 Issue 2 Pg. 219-24 (Feb 2008) ISSN: 1347-8613 [Print] Japan
• PMID: 18270474 (Publication Type: Journal Article)

Chemical References

• Benzimidazoles
• Camphanes
• Cnr2 protein, rat
• N-((1S)-1-(aminocarbonyl)-2,2-dimethylpropyl)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
• Pyrazoles
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2
• SR 144528
• Trinitrobenzenesulfonic Acid
• Cyclic AMP

Topics

• Animals
• Benzimidazoles (blood, pharmacokinetics, therapeutic use)
• CHO Cells
• Camphanes (blood, pharmacokinetics, pharmacology)
• Cell Line
• Cricetinae
• Cricetulus
• Cyclic AMP (metabolism)
• Humans
• Irritable Bowel Syndrome (chemically induced, drug therapy, metabolism)
• Male
• Pain (chemically induced, drug therapy, metabolism)
• Pyrazoles (blood, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1 (metabolism)
• Receptor, Cannabinoid, CB2 (agonists, antagonists & inhibitors, metabolism)
• Trinitrobenzenesulfonic Acid