Antipsychotic effect of the alpha–3 subunit selective benzodiazepine agonist ELB139 in rats

ELB139 (1-(p-chlorphenyl)–4-piperidin–1-yl–1,5-dihydro-imidazo–2-on) is a novel agonist for the benzodiazepine binding site of GABA_A receptor with selectivity for the alpha–3 subunit. The compound has potent anxiolytic and anticonvulsant activity at doses not exhibiting side-effects. For further characterisation the effect of ELB139 was tested in the amphetamine-induced hyperactivity and the MK–801-induced psychosis model in rats. To get insight in the mechanism of antipsychotic activity, the effect was antagonized by the benzodiazepine antagonist flumazenil and dopamine and its metabolites were determined in striatum and PFC by microdialysis.

ELB139 showed an effect in both animal models of psychosis starting at 10mg/kg and being significant at 30mg/kg p.o.. Diazepam was not effective at an anxiolytic but non-sedative dose (1mg/kg i.p.). The antipsychotic effect of ELB139 was reversed by flumazenil. There was no effect on extracellular dopamine in striatum and PFC and only a slight increase of HVA and DOPAC.

The data indicate that alpha–3 containing GABA receptors may have an unexpected antipsychotic potential. As the pharmacological activity could be observed in the absence of relevant changes in the dopamine system, these data hint at ELB139 being an antipsychotic drug with a profile different from classical drugs. ELB139 is currently undergoing phase II clinical trials in anxiety patients.

Supported by EU fund (EFRE) and the Free State of Saxony, SAB 8093