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

Yona Geffen, Abraham Nudelman, Irit Gil-Ad, Ada Rephaeli, Mei Huang, Kinneret Savitsky, Leah Klapper, Ilan Winkler, Herbert Y. Meltzer, Abraham Weizman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Reduced brain γ-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 (D2L Kiz = 0.066 nM, D2S Ki = 0.062 nM, 5-HT2A Ki = 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 agsonist that releases cortical DA and antagonizes amphetamine-induced hyperactivity with reduced catalepsy and sedation.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalEuropean Neuropsychopharmacology
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2009

Keywords

  • Antipsychotics
  • Dopamine
  • GABA
  • Perphenazine
  • Schizophrenia
  • Serotonin

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Pharmacology (medical)

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