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)