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 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.
Adage
Tiziana
T
Merck Serono Ivrea Research Center, RBM S.p.a., Colleretto Giacosa, Italy. Tiziana.Adage@MerckSerono.net
Trillat
Anne-Cécile
AC
Quattropani
Anna
A
Perrin
Dominique
D
Cavarec
Laurent
L
Shaw
Jeffrey
J
Guerassimenko
Oxana
O
Giachetti
Claudio
C
Gréco
Béatrice
B
Chumakov
Ilya
I
Halazy
Serge
S
Roach
Arthur
A
Zaratin
Paola
P
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D003124:Colorimetry; D050804:D-Aspartate Oxidase / Q000037:antagonists & inhibitors / Q000235:genetics; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D005998:Glycine / Q000378:metabolism; D006213:Hallucinogens / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry; D013216:Reflex, Startle / Q000187:drug effects; D012694:Serine / Q000378:metabolism
D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D006213:Hallucinogens; D011720:Pyrazoles; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D012694:Serine; D000594:Amino Acid Oxidoreductases; D050804:D-Aspartate Oxidase; D010622:Phencyclidine; D005998:Glycine; C005210:5-methylpyrazole-3-carboxylic acid