Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6259316 | Behavioural Brain Research | 2013 | 10 Pages |
Previous behavioral and receptor binding studies on N-phenylpiperazine derivatives by our group indicated that LASSBio-579, LASSBio-580 and LASSBio-581 could be potential antipsychotic lead compounds. The present study identified LASSBio-579 as the most promising among the three compounds, since it was the only one that inhibited apomorphine-induced climbing (5Â mg/kg p.o.) and apomorphine-induced hypothermia (15Â mg/kg p.o.). Furthermore, LASSBio-579 (0.5Â mg/kg p.o.) was effective in the ketamine-induced hyperlocomotion test and prevented the prepulse inhibition deficits induced by apomorphine, DOI and ketamine with different potencies (1Â mg/kg, 0.5Â mg/kg and 5Â mg/kg p.o., respectively). LASSBio-579 also induced a motor impairment, catalepsy and a mild sedative effect but only at doses 3-120 times higher than those with antipsychotic-like effects. In addition, LASSBio-579 (0.5 and 1Â mg/kg p.o.) reversed the catalepsy induced by WAY 100,635, corroborating its action on both dopaminergic and serotonergic neurotransmission and pointing to the contribution of 5-HT1A receptor activation to its pharmacological profile. Moreover, co-administration of sub-effective doses of LASSBio-579 with sub-effective doses of clozapine or haloperidol prevented the apomorphine-induced climbing without induction of catalepsy. In summary, our results characterize LASSBio-579 as a multi-target ligand active in pharmacological animal models of schizophrenia, confirming that this compound could be included in development programs aiming at a new drug for treating schizophrenia.
⺠The N-phenylpiperazine LASSBio-579 is effective in a model of sensoriomotor gating. ⺠LASSBio-579 is a multi-target ligand with potential antipsychotic activity. ⺠Binding to D2, D4 and 5-HT1A receptors might account for LASSBio-579 mode of action.