Enzyme inhibitor
This systemically available KAT II inhibitor (FW = 178.19 g/mol; CAS 34783-48-7; IUPAC: (3S)-3-amino-1-hydroxy-3,4-dihydroquinolin-2(1H)- one) irreversibly inhibits kynurenine amino transferase II, or KAT II, with Ki = 23 nM, kinact/Ki 112,000 M–1 s –1 , IC50 = 263 nM, and PartitionCoefficientn-octanol/H2O = 3 x 108. This inhibitor most likely makes an enamine adduct with enzyme-bound pyridoxal-P. Rationale: Kynurenate is a tryptophan-derived endogenous antagonist for glutamate and a7-nicotinic acetylcholine receptors in the brain. Increased levels are observed postmortem in the brains of patients with a range of neurocognitive disorders, including schizophrenia. Kynurenate may well contribute to the cognitive symptoms of these conditions. Pharmacology: PF-04859989 restores glutamate release "transients" evoked by ejections of nicotine into the prefrontal cortex of rats exhibiting elevated kynurenate levels. Systemic administration of PF-04859989 30 min prior to administration of Lkynurenine (but not when administered 30 min after L-kynurenine) restores glutamatergic transients recorded up to 120 min after the administration of the KAT II inhibitor. Furthermore, the KAT-II inhibitor significantly reverses L-kynurenine-induced elevations of brain KYNA levels. The KATII inhibitor does not affect nicotine-evoked glutamatergic transients in rats not pre-treated with L-kynurenine
