DL-AP3

Glutamate receptor antagonist and HPSP inhibitor CAS# 20263-06-3

DL-AP3

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Chemical structure

DL-AP3

3D structure

Chemical Properties of DL-AP3

Cas No. 20263-06-3 SDF Download SDF
PubChem ID 177120 Appearance Powder
Formula C3H8NO5P M.Wt 169.07
Type of Compound N/A Storage Desiccate at -20°C
Synonyms DL-2-Amino-3-Phosphonopropionic Acid
Solubility Soluble to 100 mM in 1eq. NaOH
Chemical Name (2R)-2-amino-3-phosphonopropanoic acid
SMILES C(C(C(=O)O)N)P(=O)(O)O
Standard InChIKey LBTABPSJONFLPO-REOHCLBHSA-N
Standard InChI InChI=1S/C3H8NO5P/c4-2(3(5)6)1-10(7,8)9/h2H,1,4H2,(H,5,6)(H2,7,8,9)/t2-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of DL-AP3

DescriptionCompetitive group I metabotropic glutamate receptor antagonist and inhibitor of phosphoserine phosphatase.

DL-AP3 Dilution Calculator

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Preparing Stock Solutions of DL-AP3

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 5.9147 mL 29.5735 mL 59.1471 mL 118.2942 mL 147.8677 mL
5 mM 1.1829 mL 5.9147 mL 11.8294 mL 23.6588 mL 29.5735 mL
10 mM 0.5915 mL 2.9574 mL 5.9147 mL 11.8294 mL 14.7868 mL
50 mM 0.1183 mL 0.5915 mL 1.1829 mL 2.3659 mL 2.9574 mL
100 mM 0.0591 mL 0.2957 mL 0.5915 mL 1.1829 mL 1.4787 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on DL-AP3

Metabotropic glutamate receptors (mGluR1-8) are G protein-coupled receptors that function to modulate brain excitatory signaling via presynaptic, postsynaptic, and glial mechanisms. DL-AP3 is a competitive mGluR1 antagonist that demonstrates a Ki value of 298 μM and an IC50 value of 1mM for rat mGluR1α when challenged with glutamate. DL-AP3 can antagonize excitatory amino acid-induced phosphoinositide hydrolysis, induce Ca2+ mobilization in rat hippocampal slices, and inhibit phosphoserine phosphatase in rat brain cortex. At concentrations from 10-300 μM DL-AP3 has been used to characterize the role of mGluR in long-term potentiation in the hippocampus in a model of learning and memory, the release of glutamate in Parkinson’s disease, and the increased activity of mGluR implicated in fragile X syndrome.

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References on DL-AP3

Group I mGluR antagonist rescues the deficit of D1-induced LTP in a mouse model of fragile X syndrome.[Pubmed:22640474]

Mol Neurodegener. 2012 May 28;7:24.

BACKGROUND: Fragile X syndrome (FXS) is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP), encoded by the Fmr1 gene. Overactive signaling by group 1 metabotropic glutamate receptor (Grp1 mGluR) could contribute to slowed synaptic development and other symptoms of FXS. Our previous study has identified that facilitation of synaptic long-term potentiation (LTP) by D1 receptor is impaired in Fmr1 knockout (KO) mice. However, the contribution of Grp1 mGluR to the facilitation of synaptic plasticity by D1 receptor stimulation in the prefrontal cortex has been less extensively studied. RESULTS: Here we demonstrated that DL-AP3, a Grp1 mGluR antagonist, rescued LTP facilitation by D1 receptor agonist SKF81297 in Fmr1KO mice. Grp1 mGluR inhibition restored the GluR1-subtype AMPA receptors surface insertion by D1 activation in the cultured Fmr1KO neurons. Simultaneous treatment of Grp1 mGluR antagonist with D1 agonist recovered the D1 receptor signaling by reversing the subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in the Fmr1KO neurons. Treatment of SKF81297 alone failed to increase the phosphorylation of NR2B-containing N-methyl D-aspartate receptors (NMDARs) at Tyr-1472 (p-NR2B-Tyr1472) in the cultures from KO mice. However, simultaneous treatment of DL-AP3 could rescue the level of p-NR2B-Tyr1472 by SKF81297 in the cultures from KO mice. Furthermore, behavioral tests indicated that simultaneous treatment of Grp1 mGluR antagonist with D1 agonist inhibited hyperactivity and improved the learning ability in the Fmr1KO mice. CONCLUSION: The findings demonstrate that mGluR1 inhibition is a useful strategy to recover D1 receptor signaling in the Fmr1KO mice, and combination of Grp1 mGluR antagonist and D1 agonist is a potential drug therapy for the FXS.

DL-2-amino-3-phosphonopropionic acid protects primary neurons from oxygen-glucose deprivation induced injury.[Pubmed:27968708]

Bosn J Basic Med Sci. 2017 Feb 21;17(1):12-16.

Cerebral infarction is a type of ischemic stroke and is one of the main causes of irreversible brain damage. Although multiple neuroprotective agents have been investigated recently, the potential of DL-2-amino-3-phosphonopropionic acid (DL-AP3) in treating oxygen-glucose deprivation (OGD)-induced neuronal injury, has not been clarified yet. This study was aimed to explore the role of DL-AP3 in primary neuronal cell cultures. Primary neurons were divided into four groups: (1) a control group that was not treated; (2) DL-AP3 group treated with 10 muM of DL-AP3; (3) OGD group, in which neurons were cultured under OGD conditions; and (4) OGD + DL-AP3 group, in which OGD model was first established and then the cells were treated with 10 muM of DL-AP3. Neuronal viability and apoptosis were measured using Cell Counting Kit-8 and flow cytometry. Expressions of phospho-Akt1 (p-Akt1) and cytochrome c were detected using Western blot. The results showed that DL-AP3 did not affect neuronal viability and apoptosis in DL-AP3 group, nor it changed p-Akt1 and cytochrome c expression (p > 0.05). In OGD + DL-AP3 group, DL-AP3 significantly attenuated the inhibitory effects of OGD on neuronal viability (p < 0.001), and reduced OGD induced apoptosis (p < 0.01). Additionally, the down-regulation of p-Akt1 and up-regulation of cytochrome c, induced by OGD, were recovered to some extent after DL-AP3 treatment (p < 0.05 or p < 0.001). Overall, DL-AP3 could protect primary neurons from OGD-induced injury by affecting the viability and apoptosis of neurons, and by regulating the expressions of p-Akt1 and cytochrome c.

Peripheral glutamate receptors contribute to mechanical hyperalgesia in a neuropathic pain model of the rat.[Pubmed:15450364]

Neuroscience. 2004;128(1):169-76.

We hypothesized that glutamate (Glu) released from the peripheral terminals of primary afferents contributes to the generation of mechanical hyperalgesia following peripheral nerve injury. Nerve injury was performed on rats with a lumbar 5 spinal nerve lesion (L5 SNL), which was preceded by L5 dorsal rhizotomy (L5 DR) to avoid the potential central effects induced by L5 SNL through the L5 dorsal root. Mechanical hyperalgesia, as evidenced by a reduction in paw withdrawal threshold (PWT), was short-lasting (<6 days) after L5 DR, but persistent (>42 days) after L5 SNL preceded by L5 DR. When an intraplantar injection into the affected hind paw was given immediately before L5 SNL, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (20 nmol), group-I metabotropic Glu (mGlu) receptor antagonist DL-amino-3-phosphonopropionic acid (DL-AP3; 70 nmol), and selective group-II mGlu receptor agonist 4-aminopyrrolidine-2,4-dicarboxylate (APDC; 20 nmol) delayed the onset of PWT reduction for 1-4 days. However, this onset was not affected by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4,-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX; 100 nmol). When the same injection was given after L5 SNL-induced mechanical hyperalgesia had been established, MK-801 reversed the PWT reduction for 30-75 min, whereas NBQX, DL-AP3, or APDC had no effect. These results suggest that the manipulation of the peripheral Glu receptors reduces neuropathic pain, by blocking NMDA and group-I mGlu receptors and by stimulating group-II mGlu receptor during the induction phase of neuropathic pain, but only by blocking the NMDA receptor during its maintenance phase.

Intrathecal injection of glutamate receptor antagonists/agonist selectively attenuated rat pain-related behaviors induced by the venom of scorpion Buthus martensi Karsch.[Pubmed:17850839]

Toxicon. 2007 Dec 15;50(8):1073-84.

The present study investigated the involvement of spinal glutamate receptors in the induction and maintenance of the pain-related behaviors induced by the venom of scorpion Buthus martensi Karsch (BmK). (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-10-imine hydrogen maleate (MK-801; 40nmol; a non-competitive NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 40nmol; a non-NMDA receptor antagonist), dl-amino-3-phosphonopropionic acid (DL-AP3; 100nmol; a group I metabotropic glutamate receptor antagonist) and 4-aminopyrrolidine-2,4-dicarboxylate (APDC; 100nmol; a group II metabotropic glutamate receptor agonist) were employed. On intrathecal injection of glutamate receptor antagonists/agonist before BmK venom administration by 10min, BmK venom-induced spontaneous nociceptive responses could be suppressed by all tested agents. Primary thermal hyperalgesia could be inhibited by MK-801 and DL-AP3, while bilateral mechanical hyperalgesia could be inhibited by CNQX and DL-AP3 and contralateral mechanical hyperalgesia could be inhibited by APDC. On intrathecal injection of glutamate receptor antagonists/agonist after BmK venom injection by 4.5h, primary thermal hyperalgesia could be partially reversed by all tested agents, while bilateral mechanical hyperalgesia could only be inhibited by APDC. The results suggest that the role of spinal glutamate receptors may be different on the various manifestations of BmK venom-induced pain-related behaviors.

Non-competitive metabotropic glutamate 1 receptor antagonists block activity of slowly adapting type I mechanoreceptor units in the rat sinus hair follicle.[Pubmed:19596050]

Neuroscience. 2009 Oct 20;163(3):933-41.

Previous studies suggested that Group I metabotropic glutamate (mGlu) receptors play a role in mechanotransduction processes of slowly adapting type I mechanoreceptors. Using an isolated rat sinus hair follicle preparation we tested a range of compounds. Surprisingly, only non-competitive mGlu1 receptor antagonists produced profound and long-lasting depression of mechanically evoked firing. 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (YM-298198) had an IC(50) of 8.7 muM (95% CI 5.7 to 13.2 microM), representing the most potent known blocker of type I mechanoreceptors. The derivative 6-amino-N-cyclohexyl-3-methylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (desmethyl YM-298198) had a comparable potency. Another compound 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) had a similar depressant effect, although it was less potent with an approximate IC(50) of 100 microM. Between three and seven times the concentration of CPCCOEt and YM-298198 respectively was required to produce similar depressions in slowly adapting type II units. No depression, and some weak excitatory effects, were observed using the following ligands: the competitive mGlu1 receptor antagonist alpha-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA) (300 microM), the phosphoserine phosphatase inhibitor dl-2-amino-3-phosphonopropionic acid (DL-AP3) (2 mM), non-competitive mGlu5 receptor antagonists 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; (S)-3,5-DHPG, (S)-3,5-dihydroxyphenylglycine (MTEP) (10 microM) and 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) (100 microM), the mGlu1 receptor agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) (500 microM), and the mGlu5 receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) (1 mM). The results suggest that the non-competitive mGlu1 receptor antagonists are not acting at conventional mGlu1 receptors but at other binding sites, possibly those directly associated with mechanogated channels or on any of a number of indirect biochemical pathways. YM-298198 and related compounds may prove to be useful ligands to identify mechanosensitive channel proteins. The selective interference of type I units may provide further evidence that Merkel cells are mechanotransducers. Finally such compounds may deliver insights or treatments for Merkel cell carcinoma.

The metabotropic glutamate receptor antagonist L-2-amino-3-phosphonopropionic acid inhibits phosphoserine phosphatase.[Pubmed:8832224]

Eur J Pharmacol. 1996 Jun 27;307(2):219-25.

Phosphoserine phosphatase catalyzes the final step in the major pathway of L-serine biosynthesis in brain. Using D-phosphoserine as substrate, the metabotropic glutamate receptor antagonist L-2-amino-3-phosphonopropionic acid (L-AP3) inhibits phosphoserine phosphatase partially purified from rat brain with a Ki of 151 microM. In contrast to AP3 enantioselectivity at metabotropic receptors, D-AP3 (Ki 48 microM) is more potent as an inhibitor of phosphoserine phosphatase than L-AP3, whereas DL-AP3 has intermediate potency. D-, L-, and DL-AP3 are 6- to 8-fold more potent inhibitors using D-phosphoserine rather than L-phosphoserine as substrate, suggesting that AP3 may have selectivity for isoforms of phosphoserine phosphatase which preferentially cleave D-phosphoserine. D-AP3 decreases the apparent affinity of D- and L-phosphoserine with little or no change in maximal velocity indicating that it is a competitive inhibitor of the enzyme. Whereas L-AP3 has similar potency at metabotropic glutamate receptors and phosphoserine phosphatase, D-AP3 is selective for phosphoserine phosphatase and is the most potent and only known competitive inhibitor of this enzyme.

L-2-amino-3-phosphonopropionic acid competitively antagonizes metabotropic glutamate receptors 1 alpha and 5 in Xenopus oocytes.[Pubmed:7621916]

Eur J Pharmacol. 1995 Apr 28;289(2):395-7.

The aspartate analog 2-amino-3-phosphonopropionic acid (AP3) antagonizes glutamate-stimulated phosphatidyl inositide hydrolysis in brain slices, but is reportedly weak or ineffective in antagonizing the phosphatidyl inositide-coupled cloned metabotropic glutamate receptors 1 alpha and 5. Thus we examined the pharmacological properties of AP3 on mGlu1 alpha and mGlu5 receptor responses in Xenopus oocytes. DL-AP3 antagonized mGlu1 alpha and mGlu5 responses, but antagonism was overcome at high glutamate concentrations consistent with competitive inhibition (IC50 = 2.1 mM for mGlu1 alpha). Both responses were also inhibited by (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG). We conclude that the available antagonists cannot distinguish between the mGlu1 alpha receptor and mGlu5 receptor, and that antagonism by AP3 may be obscured in the presence of high agonist concentrations or in cells with spare receptors.

The effects of a series of omega-phosphonic alpha-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations.[Pubmed:7042024]

Br J Pharmacol. 1982 Jan;75(1):65-75.

1 The depressant actions on evoked electrical activity and the excitant amino acid antagonist properties of a range of omega-phosphonic alpha-carboxylic amino acids have been investigated in the isolated spinal cord preparations of the frog or immature rat. 2 When tested on dorsal root-evoked ventral root potentials, members of the homologous series from 2- amino-5-phosphonovaleric acid to 2-amino-8-phosphonooctanoic acid showed depressant actions which correlated with the ability of the substances to antagonize selectivity motoneuronal depolarizations induced by N-methyl-D-aspartate. 3 2-Amino-5-phosphonovalerate was the most potent substance of the series giving an apparent KD of 1.4 microM for the antagonism of responses to N-methyl-D-aspartate. 4 A comparison of the (+)- and (-)-forms of 2-amino-5-phosphonovalerate indicated that the N-methyl-D-aspartate antagonist activity and the neuronal depressant action of this substance were both due mainly to the (-)-isomer. 5 The (-)- and (+)-forms of 2-amino-4-phosphonobutyrate had different actions. The (-)-forms of this substance had a relatively weak and non-selective antagonist action on depolarizations induced by N-methyl-D-aspartate, quisqualate and kainate and a similarly weak depressant effect when tested on evoked electrical activity. The (+)-form was more potent than he (-)-form in depressing electrically evoked activity but did not antagonize responses to amino acid excitants. At concentrations higher than those required to depress electrically evoked activity, the (+)-form produced depolarization. This action was blocked by 2-amino-5-phosphonovalerate.

Description

Phosphoserine phosphatase inhibitor

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