KB-5492

We studied the receptor binding profile of 4-methoxyphenyl 4-(3,4,5-trimethoxybenzyl)-1-piperazine acetate monofumarate monohydrate (KB-5492), a novel anti-ulcer agent, for the sigma receptor in guinea-pig brain membranes. KB-5492 selectively inhibited specific [3H]1,3-di(2-tolyl)guanidine (DTG) binding to the sigma receptor (IC50 = 3.15 microM) with a pseudo-Hill coefficient of 0.33. Computer-assisted analysis revealed that KB-5492 bound to high- and low-affinity sites. Although KB-5492 had weak affinity for alpha 2-adrenoceptors at 10 microM, it was almost inactive at a concentration of 10 microM in 33 other binding assays for receptors, second messenger systems and ion channels. sigma Receptor ligands such as haloperidol, DTG, (+)-3-(3-hydroxyphenol)-N-(1-propyl)piperidine (3-PPP), rimcazole and (-)-3-PPP inhibited specific [3H]DTG binding and their IC50 values were 0.003, 0.044, 0.33, 0.67 and 1.03 microM, respectively. On the other hand, various anti-ulcer agents such as cetraxate, cimetidine, omeprazole, sofalcone, sucralfate, teprenone and troxipide could hardly displace specific [3H]DTG binding at 100 microM. Scatchard-Rosenthal analysis indicated that [3H]DTG bound to a single site, and KD and Bmax values for [3H]DTG were 87.3 nM and 679.3 fmol/mg protein, respectively. KB-5492 significantly decreased the Bmax value, but did not affect the KD value. In contrast, haloperidol and DTG significantly increased the KD values, but did not affect the Kmax values. These findings indicate that KB-5492 selectively bound to the [3H]DTG-labeled sigma receptor and that other anti-ulcer agents had little affinity for the sigma receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

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.