In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties.

Abstract

Non-competitive N-methyl-d-aspartate (NMDA) blockers induce schizophrenic-like behavior in healthy volunteers and exacerbate symptomatology in schizophrenic patients. Hence, a compound able to enhance NMDA neurotransmission by increasing levels of d-serine, an endogenous full agonist at the glycine site of the NMDA receptors, could have anti-psychotic activity. One way to increase d-serine levels is the inhibition of d-amino acid oxidase (DAAO), the enzyme responsible for d-serine oxidation. Indeed AS057278, a potent in vitro (IC(50)=0.91 microM) and ex vivo (ED(50)=2.2-3.95 microM) DAAO inhibitor, was able to increase d-serine fraction in rat cortex and midbrain (10 mg/kg i.v.). AS057278 was able to normalize phencyclidine (PCP)-induced prepulse inhibition after acute (80 mg/kg) and chronic (20 mg/kg b.i.d.) oral administration in mice. Finally, AS057278 after oral chronic treatment (10 mg/kg b.i.d.) was able to normalize PCP-induced hyperlocomotion. These results suggest that AS057278 has the potential to anti-psychotic action toward both cognitive and positive symptoms of schizophrenia.

• Authors: Tiziana Adage, Anne-Cécile Trillat, Anna Quattropani, Dominique Perrin, Laurent Cavarec, Jeffrey Shaw, Oxana Guerassimenko, Claudio Giachetti, Béatrice Gréco, Ilya Chumakov, Serge Halazy, Arthur Roach, Paola Zaratin
• Journal: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology (Eur Neuropsychopharmacol) Vol. 18 Issue 3 Pg. 200-14 (Mar 2008) ISSN: 0924-977X [Print] Netherlands
• PMID: 17681761 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• Enzyme Inhibitors
• Hallucinogens
• Pyrazoles
• Receptors, N-Methyl-D-Aspartate
• Recombinant Proteins
• Serine
• Amino Acid Oxidoreductases
• D-Aspartate Oxidase
• Phencyclidine
• Glycine
• 5-methylpyrazole-3-carboxylic acid

Topics

• Amino Acid Oxidoreductases (antagonists & inhibitors)
• Animals
• Antipsychotic Agents (pharmacology)
• Cell Line
• Cerebral Cortex (metabolism)
• Colorimetry
• D-Aspartate Oxidase (antagonists & inhibitors, genetics)
• Enzyme Inhibitors (pharmacokinetics, pharmacology)
• Escherichia coli (enzymology)
• Glycine (metabolism)
• Hallucinogens (pharmacology)
• Injections, Intravenous
• Male
• Mesencephalon (metabolism)
• Motor Activity (drug effects)
• Phencyclidine (pharmacology)
• Plasmids (genetics)
• Pyrazoles (pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (drug effects)
• Recombinant Proteins (chemistry)
• Reflex, Startle (drug effects)
• Serine (metabolism)