title: 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.affiliation: Discovery Research, Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Inc., Chita-gun, Aichi, Japan. akiraki9@gmail.com
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Katsuyo
authors.initials: K
authors.lastname: Ohashi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sugie
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Omura
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016466:CHO Cells; D001892:Camphanes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D001562:Benzimidazoles; D001892:Camphanes; C469526:Cnr2 protein, rat; C529026:N-((1S)-1-(aminocarbonyl)-2,2-dimethylpropyl)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D014302:Trinitrobenzenesulfonic Acid; D000242:Cyclic AMP