BL-1020: a novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia.

摘要

Reduced brain gamma-amino-butyric acid (GABA) participates in the pathogenesis of schizophrenia. GABA scarcely penetrates the brain. We evaluated the pharmacological properties of BL-1020, a novel GABA ester of perphenazine. Oral BL-1020 or perphenazine were assessed in acute and subchronic schizophrenia rat models. Catalepsy, serum prolactin, receptor binding profile and cortical (PFC), hippocampal (Hip) and dopamine (DA) levels were determined. Radioactive [14C] labeled BL-1020 was used for pharmacokinetics (PK). Acute and subchronic treatment with BL-1020 antagonized amphetamine-induced hyperactivity, with significantly lower catalepsy and sedation compared to equimolar perphenazine. At the same time, BL-1020 increased DA release in the PFC and Hip. BL-1020 and perphenazine stimulated prolactin secretion equally. BL-1020 displayed strong DA and serotonin (5HT) receptor inhibition (D(2L)K(iz)=0.066 nM, D(2S)K(i)=0.062 nM, 5-HT(2A)K(i)=0.21 nM). PK data revealed that BL-1020 penetrated the brain. CONCLUSIONS: The advantages of BL-1020 for treatment of schizophrenia stem from its being a DA/5HT antagonist and a GABAergic agonist that releases cortical DA and antagonizes amphetamine-induced hyperactivity with reduced catalepsy and sedation.