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

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 enclogenous 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 (IC50=0.91 mu M) and ex vivo (ED50=2.2-3.95 mu M) 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. (c) 2007 Elsevier B.V. and ECNP. All rights reserved.