NEUROPHARMACOLOGICAL PROFILE OF EMD-57445, A SIGMA-RECEPTOR LIGAND WITH POTENTIAL ANTIPSYCHOTIC ACTIVITY

EMD 57445 -1-ylmethyl]-3-(4-methoxyphenyl)-oxazolidin-2-one) is a new sigma receptor ligand with only marginal affinity for many other (incl uding dopamine) receptors. In the present study, central, particularly neuroleptic-like, effects of this compound were evaluated and compare d with those of another sigma receptor ligand, rimcazole. EMD 57445 de creased locomotor activity in rats and mice. The amphetamine-induced l ocomotor hyperactivity and stereotypy were reduced by EMD 57445. The d rug 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 quinpiro le (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, 1-dihydroxy-5H-dibenzo(a,b)-cyclohepten-5,10-imine hydrogen maleate) or competitive (CGP 37849, D,L-E-amino-4-methyl-5-phosphono-3-pentenoi c acid) NMDA receptor antagonists was also inhibited. EMD 57445 decrea sed the cocaine-, morphine- or caffeine-induced locomotor hyperactivit y in rats or mice. It neither induced catalepsy nor increased muscle t one in rats. Rimcazole had somewhat different effects: it increased th e 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 u seful as an antipsychotic drug devoid of extrapyramidal side-effects.