Receptor binding profiles of KB-5492, a novel anti-ulcer agent, at sigma receptors in guinea-pig brain.

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)