title: Effect of a new alpha 2 delta ligand PD-217014 on visceral hypersensitivity induced by 2,4,6-trinitrobenzene sulfonic acid in rats.
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.
authors.affiliation: Discovery Research, Pfizer Global Research and Development, Nagoya Laboratories, Aichi, Japan.
authors.forename: Katsuyo
authors.initials: K
authors.lastname: Ohashi
authors.forename: Mitsuhisa
authors.initials: M
authors.lastname: Kawai
authors.forename: Noriko
authors.initials: N
authors.lastname: Ninomiya
authors.forename: Charles
authors.initials: C
authors.lastname: Taylor
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kurebayashi
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008297:Male; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity*; D014781:Viscera / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C527477:1 alpha,3 alpha,5 alpha-3-aminomethyl-bicyclo(3.2.0)heptane-3-acetic acid; D000700:Analgesics; D001643:Bridged Bicyclo Compounds; C486060:Cacna2d1 protein, rat; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D008024:Ligands; D005680:gamma-Aminobutyric Acid; D014302:Trinitrobenzenesulfonic Acid