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| Targets |
mGluR5, a Gq-coupled receptor highly expressed in the hippocampus and cortex. (R)-ADX-47273 binds to an allosteric site distinct from the glutamate-binding domain, increasing the affinity of glutamate for the receptor and enhancing downstream signaling (PLC, IP3, Ca2+). This positive modulation potentiates long-term potentiation (LTP) and enhances learning and memory. It does not activate the receptor on its own.
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| ln Vitro |
(R)-ADX-47273 (ADX-47273 (5)) is a strong positive allosteric modulator of mGluR5 wth an increasing EC50 of 168 nM and a 9-fold change in the glutamate response curve at 1 μM[1].
In vitro, (R)-ADX-47273 potentiates glutamate-induced calcium mobilization in HEK-293 cells expressing mGluR5 with an EC50 of 168 nM. At 10 µM, it shows >50-fold selectivity over other mGluR subtypes (mGluR1, 2, 3, 4, 6, 7, 8). It also enhances NMDA receptor-dependent LTP in rat hippocampal slices and increases phosphorylation of ERK and CREB. The compound does not affect basal synaptic transmission or cell viability up to 30 µM. |
| ln Vivo |
In vivo, (R)-ADX-47273 (10–30 mg/kg, i.p. or p.o.) reverses MK-801-induced deficits in novel object recognition and social interaction in rats, indicating antipsychotic-like activity. In mice, it improves performance in the Morris water maze and contextual fear conditioning. It also reduces hyperlocomotion induced by amphetamine. These effects are consistent with mGluR5 PAM activity and support its potential for treating cognitive deficits in schizophrenia and Alzheimer's disease.
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| Enzyme Assay |
Cell-free binding assays use membranes from HEK-293 cells expressing mGluR5. Incubate with [3H]MPEP (a negative allosteric modulator) or [3H]glutamate in the presence of varying (R)-ADX-47273 to determine allosteric binding. For functional potentiation, measure [3H]inositol phosphate accumulation in membrane preparations incubated with glutamate (EC20) and varying compound, and quantify IP1 by HTRF. Potentiation EC50 is derived.
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| Cell Assay |
Cells expressing mGluR5 (e.g., HEK-293 or primary cortical neurons) are loaded with Fluo-4 and stimulated with a submaximal concentration of glutamate (EC20) in the presence of increasing concentrations of (R)-ADX-47273. Calcium flux is recorded on a plate reader. The EC50 for potentiation is calculated. For selectivity, similar assays are performed with cells expressing other mGluR subtypes. LTP is measured in acute hippocampal slices using field potential recordings.
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| Animal Protocol |
In vivo, (R)-ADX-47273 is administered intraperitoneally (3, 10, 30 mg/kg) or orally (10–30 mg/kg) in male Sprague-Dawley rats. For cognitive studies, rats are trained in novel object recognition or Morris water maze; compound is given 30–60 min before testing. For schizophrenia models, MK-801 (0.1 mg/kg) is co-administered, and locomotor activity or social interaction is measured. Brain and plasma samples are collected for pharmacokinetic analysis.
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| ADME/Pharmacokinetics |
Molecular formula C20H17F2N3O2, MW 369.36. Appearance: solid. Solubility: DMSO (≥20 mg/mL). Storage: -20°C, stable for 3 years in powder form. Purity >98%. For in vivo, dissolve in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% saline (1 mg/mL). LogP ~3.5, plasma protein binding ~90%. Half-life in rats ~2 h after i.p. administration.
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| Toxicity/Toxicokinetics |
No published toxicology data. In preclinical studies, no overt toxicity was observed at doses up to 30 mg/kg. Potential side effects of mGluR5 PAMs may include seizure exacerbation at high doses, though this is less common than with agonists. Standard safety pharmacology (hERG, respiratory, CNS) would be required for clinical development. No genotoxicity data available.
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| References | |
| Additional Infomation |
(R)-ADX-47273 is a research compound, not FDA-approved. It is widely used to study mGluR5 function in cognition, schizophrenia, and drug addiction. It has been instrumental in validating mGluR5 as a therapeutic target. Several mGluR5 PAMs have entered clinical trials, but (R)-ADX-47273 itself has not progressed to the clinic. Its enantiomer, (S)-ADX-47273, is less active, highlighting stereospecificity.
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| Molecular Formula |
C20H17F2N3O2
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|---|---|
| Molecular Weight |
369.364691495895
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| Exact Mass |
369.128
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| CAS # |
851881-59-9
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| Related CAS # |
ADX-47273;851881-60-2
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| PubChem CID |
11303165
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| Appearance |
White to off-white solid powder
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| LogP |
3.7
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
508
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N1=C(N=C([C@H]2CN(CCC2)C(=O)C2=CC=C(C=C2)F)O1)C1C=CC(=CC=1)F
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| InChi Key |
VXQCCZHCFBHTTD-OAHLLOKOSA-N
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| InChi Code |
InChI=1S/C20H17F2N3O2/c21-16-7-3-13(4-8-16)18-23-19(27-24-18)15-2-1-11-25(12-15)20(26)14-5-9-17(22)10-6-14/h3-10,15H,1-2,11-12H2/t15-/m1/s1
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| Chemical Name |
(4-fluorophenyl)-[(3R)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~270.74 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.77 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7074 mL | 13.5369 mL | 27.0739 mL | |
| 5 mM | 0.5415 mL | 2.7074 mL | 5.4148 mL | |
| 10 mM | 0.2707 mL | 1.3537 mL | 2.7074 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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