Effect of a new alpha 2 delta ligand PD-217014 on visceral hypersensitivity induced by 2,4,6-trinitrobenzene sulfonic acid in rats

Katsuyo Ohashi; Mitsuhisa Kawai; Noriko Ninomiya; Charles Taylor; Yoichi Kurebayashi

doi:10.1159/000110737

Effect of a new alpha 2 delta ligand PD-217014 on visceral hypersensitivity induced by 2,4,6-trinitrobenzene sulfonic acid in rats

Pharmacology. 2008;81(2):144-50. doi: 10.1159/000110737. Epub 2007 Nov 7.

Authors

Katsuyo Ohashi¹, Mitsuhisa Kawai, Noriko Ninomiya, Charles Taylor, Yoichi Kurebayashi

Affiliation

¹ Discovery Research, Pfizer Global Research and Development, Nagoya Laboratories, Aichi, Japan.

PMID: 17989503
DOI: 10.1159/000110737

Abstract

PD-217014, a new GABA analog (1 alpha,3 alpha,5 alpha-3-aminomethyl-bicyclo[3.2.0]heptane-3-acetic acid), inhibited [(3)H]-gabapentin binding to alpha(2)delta subunit of voltage-gated calcium channels in a concentration-dependent manner (K(i) = 18 nmol/l). Oral treatment with PD-217014 significantly inhibited the visceral hypersensitivity induced by an intra-colonic injection of trinitrobenzene sulfonic acid in rats. The anti-hyperalgesic effect of PD-217014 increased in a dose-dependent manner, and reached a plateau level at 60 mg/kg p.o. The visceral analgesia produced by PD-217014 at 30 and 60 mg/kg p.o. correlated with blood concentrations within 4 h after dosing, and maximal efficacy was obtained 2 h after dosing when the maximal blood concentration was achieved at either dose. These results indicate that PD-217014 is a potent alpha(2)delta ligand and possesses visceral analgesic activity.

Publication types

Comparative Study

MeSH terms

Analgesics / chemistry
Analgesics / pharmacology
Analgesics / therapeutic use
Animals
Binding Sites / drug effects
Bridged Bicyclo Compounds / pharmacology*
Bridged Bicyclo Compounds / therapeutic use
Calcium Channels / metabolism*
Calcium Channels, L-Type
Dose-Response Relationship, Drug
Hyperalgesia / drug therapy*
Hyperalgesia / metabolism
Hyperalgesia / pathology
Ligands
Male
Pain Measurement / drug effects
Pain Measurement / methods
Rats
Rats, Sprague-Dawley
Swine
Trinitrobenzenesulfonic Acid / toxicity*
Viscera / drug effects*
Viscera / metabolism
Viscera / pathology
gamma-Aminobutyric Acid / analogs & derivatives*
gamma-Aminobutyric Acid / pharmacology
gamma-Aminobutyric Acid / therapeutic use

Substances

1 alpha,3 alpha,5 alpha-3-aminomethyl-bicyclo(3.2.0)heptane-3-acetic acid
Analgesics
Bridged Bicyclo Compounds
Cacna2d1 protein, rat
Calcium Channels
Calcium Channels, L-Type
Ligands
gamma-Aminobutyric Acid
Trinitrobenzenesulfonic Acid