MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]++ +methy l-2-
pyrrolidinone L-
tartrate) is a novel selective
sigma receptor ligand, currently being developed for the treatment of
schizophrenia.
MS-377 showed anti-
phencyclidine (PCP), anti-dopaminergic and anti-serotonergic activities, and we anticipated that the anti-psychotic activities of
MS-377 were associated with sigma(1) receptors. However, its pharmacological profile is partly distinct from those of selective sigma(1) receptor
ligands. Thus, one of the possible speculations is that
MS-377 has another site of action. In the present study, we examined the binding properties of radiolabeled
MS-377 ([3H]
MS-377) to rat brain membranes. [3H]
MS-377 showed saturable and reversible binding to rat brain membranes. Scatchard plot and Hill plot from saturation studies were linear, with K(d) of 15.2+/-6.6 nM, B(max) of 599.4+/-58.6 fmol/mg
protein and Hill coefficient of 1.01+/-0.01, indicating that [3H]
MS-377 bound to a single high-affinity site in rat brain membranes. Displacement studies revealed that the other sigma reference compounds with different structures inhibited the specific binding of [3H]
MS-377 in a competitive manner. Stereoselectivity was observed for the inhibition of [3H]
MS-377 binding, (+)-isomers were more potent than (-)-isomers. Non-
sigma receptor ligand PCP showed weak inhibition of [3H]
MS-377 binding. The rank order of potency for the sigma reference compounds to displace [3H]
MS-377 binding were as following:
haloperidol>
MS-377=(+)-
pentazocine>DTG (1, 3-Ditolylguanidine)=(-)-
pentazocine>BMY14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyramidinyl)-1-
piperazine butanol)>(+)-SKF-10,047>(-)-SKF-10,047=PCP. These results suggested that the
MS-377 selectively binds to sigma binding site with high affinity in rat brain membranes. Therefore, the anti-psychotic activities of
MS-377 are attributable to association with sigma(1) receptors.