AS057278
(Synonyms: 5-甲基-1H-吡唑-3-羧酸) 目录号 : GC64909AS057278 (3-Methylpyrazole-5-carboxylic acid, MPC) is an inhibitor of D-amino acid oxidase (DAAO).
Cas No.:402-61-9
Sample solution is provided at 25 µL, 10mM.
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AS057278 (3-Methylpyrazole-5-carboxylic acid, MPC) is an inhibitor of D-amino acid oxidase (DAAO).
No inhibitory effect on DASOX were observed with AS057278 at the concentration of 10 μM and no inhibitory effect on serine racemase were observed with AS057278 at the concentration of 50 μM[2].
MPC is able to increase brain d-serine levels and ameliorate PCP-induced abnormal behavior in SD rat[1]. MPC increaseS 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. AS057278 after oral chronic treatment (10 mg/kg b.i.d.) was able to normalize PCP-induced hyperlocomotion[2].
[1] Haruta N, et al. Proc Jpn Acad Ser B Phys Biol Sci. 2011, 87(10):641-8. [2] Adage T, et al. Eur Neuropsychopharmacol. 2008, 18(3):200-14.
Cas No. | 402-61-9 | SDF | Download SDF |
别名 | 5-甲基-1H-吡唑-3-羧酸 | ||
分子式 | C5H6N2O2 | 分子量 | 126.11 |
溶解度 | 储存条件 | Store at -20°C | |
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1 mg | 5 mg | 10 mg | |
1 mM | 7.9296 mL | 39.6479 mL | 79.2959 mL |
5 mM | 1.5859 mL | 7.9296 mL | 15.8592 mL |
10 mM | 0.793 mL | 3.9648 mL | 7.9296 mL |
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In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties
Eur Neuropsychopharmacol 2008 Mar;18(3):200-14.PMID:17681761DOI:10.1016/j.euroneuro.2007.06.006.
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.
A series of D-amino acid oxidase inhibitors specifically prevents and reverses formalin-induced tonic pain in rats
J Pharmacol Exp Ther 2011 Jan;336(1):282-93.PMID:20952482DOI:10.1124/jpet.110.172353.
We have found that mutation of D-amino acid oxidase (DAO) diminished formalin-induced tonic pain. The present research further studied the analgesic effects of a series of DAO inhibitors in this model. 5-Chlorobenzo[d]isoxazol-3-ol (CBIO), 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (compound 8), 5-methylpyrazole-3-carboxylic acid (AS057278), sodium benzoate, and 4-nitro-3-pyrazole carboxylic acid (NPCA) inhibited rat spinal cord-derived DAO activity in a concentration-dependent manner, with maximal inhibition of 100% and potency rank of CBIO > compound 8 > AS057278 > sodium benzoate > NPCA. In rats, intrathecal injections of CBIO, compound 8, AS057278, and sodium benzoate but not NPCA specifically prevented formalin-induced tonic pain but not acute nociception, with the same potency order as in the DAO activity assay. The highly potent analgesia of DAO inhibitors was evidenced by CBIO, which prevented 50% pain at 0.06 μg, approximately 5-fold the potency of morphine. CBIO given after formalin challenge also reversed the established pain state to the same degree as prevention. The antihyperalgesic potencies of these DAO inhibitors were highly correlated to their inhibitions of spinal DAO activity. Maximum inhibition of pain by these compounds was approximately 60%, comparable with that of the N-methyl-D-aspartic acid receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), suggesting that a larger portion of formalin-induced tonic pain is "DAO-sensitive," whereas the remaining 40% of tonic pain and acute nociception is "DAO-insensitive." These findings, combined with our previous DAO gene mutation and induction results, indicate spinal DAO mediates both induction and maintenance of formalin-induced tonic pain and further validate spinal DAO as a novel and efficacious target molecule for the treatment of chronic pain.
Commentary: genome-based CNS drug discovery: D-amino acid oxidase (DAAO) as a novel target for antipsychotic medications: progress and challenges
Biochem Pharmacol 2009 Dec 1;78(11):1360-5.PMID:19591808DOI:10.1016/j.bcp.2009.06.108.
Antipsychotics, the drugs used currently for the treatment of schizophrenia, produce their therapeutic effects via the blockade of dopamine receptors. These compounds are, however, limited in their therapeutic efficacy and have side effect liabilities that also limit their use. Agents that produce antipsychotic effects by enhancing NMDA receptor function represent a viable alternative to dopamine antagonists. D-serine, is the prototype of this approach acting as a positive allosteric modulator of the NMDA receptor to enhance antipsychotic efficacy in the clinic. A newer approach to modulating NMDA receptor function, identified by gene association studies, is pLG72/DAOA (D-amino acid oxidase activator) a peptide that modulates D-amino acid oxidase (DAAO) activity, increasing endogenous levels of D-serine. While the initial association of DAOA with schizophrenia and its functional effects on DAAO activity have not been replicated, its identification has led to the development of several DAAO inhibitors, e.g., AS057278, CBIO and Compound 8, that are active in animal models of antipsychotic action. The complications in validating the G72 association with schizoprenia highlight the inherent challenges in translating gene-based, disease-related associations to drug discovery targets.
Identification of a novel spinal dorsal horn astroglial D-amino acid oxidase-hydrogen peroxide pathway involved in morphine antinociceptive tolerance
Anesthesiology 2014 Apr;120(4):962-75.PMID:23928652DOI:10.1097/ALN.0b013e3182a66d2a.
Background: D-Amino acid oxidase (DAAO) is a flavin adenine dinucleotide-dependent peroxisomal flavoenzyme which is almost exclusively expressed within astrocytes in the spinal cord. DAAO catalyzes oxidation of D-amino acids to hydrogen peroxide, which is a stable and less active reactive oxygen species, and may represent a final form of reactive oxygen species. This study tested the hypothesis that the spinal astroglial DAAO-hydrogen peroxide pathway plays an important role in the development of morphine antinociceptive tolerance. Methods: Rat and mouse formalin, hot-plate, and tail-flick tests were used, and spinal DAAO expression and hydrogen peroxide level were measured. Sample size of animals was six in each study group. Results: Subcutaneous and intrathecal DAAO inhibitors, including 5-chloro-benzo[d]isoxazol-3-ol, AS057278, and sodium benzoate, completely prevented and reversed morphine antinociceptive tolerance in the formalin, hot-plate, and tail-immersion tests, with a positive correlation to their DAAO inhibitory activities. Intrathecal gene silencers, small interfering RNA/DAAO and small hairpin RNA/DAAO, almost completely prevented morphine tolerance. Intrathecal 5-chloro-benzo[d]isoxazol-3-ol and small interfering RNA/DAAO completely prevented increased spinal hydrogen peroxide levels after chronic morphine treatment. Intrathecal nonselective hydrogen peroxide scavenger phenyl-tert-N-butyl nitrone and the specific hydrogen peroxide catalyst catalase also abolished established morphine tolerance. Spinal dorsal horn astrocytes specifically expressed DAAO was significantly up-regulated, accompanying astrocyte hypertrophy after chronic morphine treatment. Conclusions: For the first time, the authors' result identify a novel spinal astroglial DAAO-hydrogen peroxide pathway that is critically involved in the initiation and maintenance of morphine antinociceptive tolerance, and suggest that this pathway is of potential utility for the management of morphine tolerance and chronic pain.
Changes in extracellular kynurenic acid concentrations in rat prefrontal cortex after D-kynurenine infusion: an in vivo microdialysis study
Neurochem Res 2010 Apr;35(4):559-63.PMID:19941066DOI:10.1007/s11064-009-0099-1.
Using a microdialysis technique, we continuously infused D-kynurenine (KYN) (0, 50, and 100 microM) into the prefrontal cortices (PFCs) of male Sprague-Dawley rats. We then used column-switching high-performance liquid chromatography to assess the alterations in the concentration of kynurenic acid (KYNA)-an antagonist of N-methyl-D-aspartate and alpha7 nicotinic acetylcholine receptors-in the extracellular fluid in the PFC. Local infusion of D-KYN into the PFC remarkably increased the extracellular KYNA concentration, indicating that D-KYN is metabolized to KYNA in the PFC. The D-KYN-induced increase in KYNA levels was significantly attenuated by the co-administration of 3-methylpyrazole-5-carboxylic acid (AS057278)-a specific inhibitor of D-amino acid oxidase (DAAO). These results suggest that DAAO may be involved in the production of KYNA from D-KYN in the PFC in vivo.