Binding properties of KB-5492, a novel anti-ulcer agent, at sigma receptors in porcine gastric fundic mucosa.

Abstract

We examined the effects of KB-5492, 4-methoxyphenyl 4-(3,4,5-trimethoxybenzyl)-1-piperazine acetate monofumarate monohydrate, a novel anti-ulcer agent and a selective sigma receptor ligand, on specific [3H](+)-N-allyl-normetazocine (SKF 10,047) and [3H]1,3-di(2-tolyl)guanidine (DTG) binding in porcine gastric fundic mucosa. KB-5492 inhibited specific [3H](+)-SKF 10,047 binding in a competitive manner and specific [3H]DTG binding in a non-competitive manner. The Ki value of KB-5492 on specific [3H]DTG binding (Ki = 4.6 microM) was 8.4-fold higher than that on specific [3H](+)-SKF 10,047 binding (Ki = 0.55 microM). Computer-assisted analysis of the displacement curve of KB-5492 for specific [3H]DTG binding indicated the best fit for a two-site model rather than a one-site model, but not for specific [3H](+)-SKF 10,047 binding. Anti-ulcer agents such as omeprazole, cetraxate, cimetidine, sofalcone, sucralfate, teprenone and troxipide had weak or little effect on specific [3H](+)-SKF 10,047 and [3H]DTG binding at a concentration of 100 microM, except that omeprazole exhibited a low affinity for specific [3H](+)-SKF 10,047 binding. These findings suggest that KB-5492 is a unique anti-ulcer agent which binds to sigma receptors in porcine gastric fundic mucosa.