Sigma receptor-mediated effects of a new antiulcer agent, KB-5492, on experimental gastric mucosal lesions and gastric alkaline secretion in rats.
Using in vitro receptor autoradiography, we found specific [3H] 1,3-di(2-tolyl)guanidine (DTG) binding to be highly localized in the mucosa of the stomach and duodenum in rats. 4-Methoxyphenyl 4-(3,4,5-trimethoxybenzyl)-1-piperazine acetate monofumarate monohydrate (KB-5492), a novel antiulcer agent and a specific sigma receptor ligand, at 1 and 10 microM inhibited this specific [3H] DTG binding in rat stomach. The effects of KB-5492 and sigma receptor ligands such as DTG and rimcazole on the gastric lesions and alkaline secretion in rats were examined. KB-5492 (25-100 mg/kg, p.o.), DTG (3-30 mg/kg, p.o.) and rimcazole (30-100 mg/kg, p.o.) inhibited ethanol-induced and water-immersion stress-induced gastric mucosal lesions in rats. KB-5492 (30 mg/kg, i.g.) and DTG (30 mg/kg, i.g.) increased the gastric alkaline secretion in rats. These protective and alkaline-stimulated effects of KB-5492 and DTG were attenuated by haloperidol, a sigma receptor antagonist. These findings suggest that KB-5492 and DTG exert ulceroprotective effects through interaction with sigma receptors in the gastric mucosa.
Hara
H
H
Department of Pharmacology, New Drug Research Laboratories, Kanebo Ltd., Osaka, Japan.
Tanaka
K
K
Harada
Y
Y
Sukamoto
T
T
D000818:Animals; D000897:Anti-Ulcer Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001345:Autoradiography; D002227:Carbazoles / Q000494:pharmacology; D000431:Ethanol / Q000037:antagonists & inhibitors; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006146:Guanidines / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects* / Q000378:metabolism; D013276:Stomach Ulcer / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D013312:Stress, Physiological
D000897:Anti-Ulcer Agents; D002227:Carbazoles; D006146:Guanidines; D010879:Piperazines; D017480:Receptors, sigma; C065167:KB 5492; D000431:Ethanol; C034931:rimcazole; D006220:Haloperidol; C050232:1,3-ditolylguanidine