Neuropharmacological profile of EMD 57445, a σ receptor ligand with potential antipsychotic activity

Abstract

EMD 57445 (( S)-(−)-[4-hydroxy-4-(3,4-benzodioxol-5-yl)-piperidin-1-ylmethyl]-3-(4-methoxyphenyl)-oxazolidin-2-one) is a new σ receptor ligand with only marginal affinity for many other (including dopamine) receptors. In the present study, central, particularly neuroleptic-like, effects of this compound were evaluated and compared with those of another σ receptor ligand, rimcazole. EMD 57445 decreased locomotor activity in rats and mice. The amphetamine-induced locomotor hyperactivity and stereotypy were reduced by EMD 57445. The drug was able to inhibit the behavioural effects induced by apomorphine, i.e., the locomotor hyperactivity, stereotypy and aggression in rats, as well as climbing in mice. The hyperlocomotion induced by quinpirole (a dopamine D 2 3 receptor agonist) and the grooming induced by SKF 38393 (a dopamine D 1 receptor agonist) were decreased by EMD 57445. The behavioural stimulation evoked in rats by non-competitive (MK-801, (+)-5-methyl-10,11-dihydroxy-5 H-dibenzo( a,b)-cyclohepten-5,10-imine hydrogen maleate) or competitive (CGP 37849, d,l-E-amino-4-methyl-5-phosphono-3-pentenoic acid) NMDA receptor antagonists was also inhibited. EMD 57445 decreased the cocaine-, morphine- or caffeine-induced locomotor hyperactivity in rats or mice. It neither induced catalepsy nor increased muscle tone in rats. Rimcazole had somewhat different effects: it increased the amphetamine stereotypy as well as the amphetamine-, quinpirole- and cocaine-induced locomotor hyperactivity in rats. The results indicate that EMD 57445 shows functional antidopaminergic activity and may be useful as an antipsychotic drug devoid of extrapyramidal side-effects.