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

Abstract

UNLABELLED:

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.

• Authors: Yona Geffen, Abraham Nudelman, Irit Gil-Ad, Ada Rephaeli, Mei Huang, Kinneret Savitsky, Leah Klapper, Ilan Winkler, Herbert Y Meltzer, Abraham Weizman
• Journal: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology (Eur Neuropsychopharmacol) Vol. 19 Issue 1 Pg. 1-13 (Jan 2009) ISSN: 1873-7862 [Electronic] Netherlands
• PMID: 18757185 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• Central Nervous System Stimulants
• perphenazine GABA ester
• gamma-Aminobutyric Acid
• Prolactin
• Amphetamine
• Perphenazine
• Acetylcholine
• Dopamine

Topics

• Acetylcholine (metabolism)
• Amphetamine (antagonists & inhibitors, toxicity)
• Animals
• Antipsychotic Agents (adverse effects, pharmacokinetics, pharmacology)
• Biological Availability
• Brain (metabolism)
• Catalepsy (chemically induced)
• Central Nervous System Stimulants (antagonists & inhibitors, toxicity)
• Dopamine (metabolism)
• Hippocampus (drug effects, metabolism)
• Male
• Microdialysis
• Motor Activity (drug effects)
• Perphenazine (adverse effects, analogs & derivatives, pharmacokinetics, pharmacology)
• Prefrontal Cortex (drug effects, metabolism)
• Prolactin (metabolism)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Schizophrenia (drug therapy)
• Tissue Distribution
• gamma-Aminobutyric Acid (adverse effects, analogs & derivatives, pharmacokinetics, pharmacology, physiology)