Evidence of changes in central noradrenergic activity has been reported in schizophrenic patients and studies indicate that activation of the α2-adrenoceptor improves memory and neuroprotection. In this study, a new
imidazolidine derivative
3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione, PT-31, a putative α2A-adrenoceptor agonist, was evaluated in mouse models predictive of efficacy in the treatment of positive and
cognitive symptoms of
schizophrenia, as well as its ability to promote cerebellar granule cell survival in vitro, in the presence or absence of
glutamate (100 µmol/l). PT-31 prevented
apomorphine-induced climbing and the
ketamine-induced hyperlocomotion, without inducing
catalepsy or motor impairment. PT-31 protected against the impairment of prepulse inhibition induced by
apomorphine, (±)-DOI, and
ketamine. The molecule did not affect mouse short nor long-term memory per se, but it protected against
ketamine-induced memory impairment when administered at different stages of the memory process (acquisition, consolidation, and retrieval) in the novel object recognition task. When added to cultured cerebellar granule neurons, PT-31 was not toxic per se and protected neurons from
glutamate-induced apoptosis. In conclusion, PT-31 displayed a preclinical pharmacology predictive of
neuroprotective effects and efficacy in relieving
schizophrenia symptoms, without inducing motor side effects, suggesting that it could represent a molecular scaffold for
antipsychotic drug development.