Binding properties of [H-3]MS-377, a novel sigma receptor ligand, to rat brain membranes

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, c urrently being developed for the treatment of schizophrenia. MS-377 showed anti-phencyclidine (PCP), anti-dopaminergic and anti-serotonegic activities , and we anticipated that the anti-psychotic activities of MS-377 were asso ciated with sigma(1) receptors. However, its pharmacological profile is par tly distinct from those of selective sigma(1) receptor ligands. Thus, one o f the possible speculations is that MS-377 has another site of action. In t he present study, we examined the binding properties of radiolabeled MS-377 ([H-3]MS-377) to rat brain membranes. [H-3]MS-377 showed saturable and rev ersible binding to rat brain membranes. Scatchard plot and Hill plot from s aturation 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 [H-3]MS-377 bound to a single high-affinity site in rat brain membrane s. Displacement studies revealed that the other sigma reference compounds w ith different structures inhibited the specific binding of [H-3]MS-377 in a competitive manner. Stereoselectivity was observed for the inhibition of [ H-3]MS-377 binding, (+)-isomers were more potent than(-)-isomers. Non-sigma receptor ligand PCP showed weak inhibition of [H-3]MS-377 binding. The ran k order of potency for the sigma reference compounds to displace [H-3]MS-37 7 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, th e anti-psychotic activities of MS-377 are attributable to association with sigma(1) receptors. (C) 2000 Elsevier Science B.V. All rights reserved.