 Chemical Structure.png)
ADX47273 (ADX-47273; BA-94673139; BA94673139) is a potent, selective and specific mGlu5 positive allosteric modulator(PAM) with important biological activity. It activates mGlu5 with an EC50 of 0.17 μM, and exhibits no activity against other mGlu subtypes. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms.
Physicochemical Properties
| Molecular Formula | C20H17F2N3O2 | |
| Molecular Weight | 369.36 | |
| Exact Mass | 369.128 | |
| CAS # | 851881-60-2 | |
| Related CAS # | (R)-ADX-47273;851881-59-9 | |
| PubChem CID | 11383075 | |
| Appearance | White to off-white solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 540.8±60.0 °C at 760 mmHg | |
| Flash Point | 280.9±32.9 °C | |
| Vapour Pressure | 0.0±1.4 mmHg at 25°C | |
| Index of Refraction | 1.580 | |
| LogP | 3.48 | |
| Hydrogen Bond Donor Count | 0 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 3 | |
| Heavy Atom Count | 27 | |
| Complexity | 508 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | C1C[C@@H](CN(C1)C(=O)C2=CC=C(C=C2)F)C3=NC(=NO3)C4=CC=C(C=C4)F |
|
| InChi Key | VXQCCZHCFBHTTD-HNNXBMFYSA-N | |
| 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-/m0/s1 | |
| Chemical Name | (4-fluorophenyl)-[(3S)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone | |
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| 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) |
Biological Activity
| Targets |
Metabotropic glutamate receptor 5 (mGluR5) (EC50 = 31 nM for potentiation of glutamate-induced calcium mobilization; no affinity for other mGluR subtypes) [1] |
| ln Vitro |
In HEK 293 cells expressing rat mGlu5, ADX-47273 (0.1 nM-10 μM; 5 min) increases the response to 50 nM glutamate in a concentration-dependent manner without eliciting a response on its own[1]. With an EC50 of 0.23 μM, ADX-47273 (0.1 nM–10 μM; 5 min) increases the response to 300 nM glutamate in primary astrocyte cultures in a concentration-dependent manner[1]. With a Ki of 4.3 μM, ADX47273 (0.01-10 μM; 60 min) inhibits the binding of [3H]MPEP to the membranes of rat mGlu5 receptor-expressing HEK cells[1]. In Chinese hamster ovary (CHO) cells expressing human mGluR5, ADX-47273 (BA 94673139) acted as a positive allosteric modulator (PAM), potentiating glutamate-induced calcium mobilization in a concentration-dependent manner with an EC50 of 31 nM. It did not activate mGluR5 in the absence of glutamate and showed no significant binding to other mGluR subtypes (mGluR1-4, 6-8) or ionotropic glutamate receptors [1] In rat hippocampal slices, ADX-47273 (BA 94673139) (1-10 μM) enhanced mGluR5-mediated long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, a cellular correlate of learning and memory. This effect was blocked by the selective mGluR5 antagonist MPEP [3] In cultured rat cortical neurons, ADX-47273 (BA 94673139) (0.1-10 μM) potentiated glutamate-induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, a downstream signaling event of mGluR5 activation, in a concentration-dependent manner [1] |
| ln Vivo |
In rat hippocampal and prefrontal cortex, ADX47273 (1–10 mg/kg; single ip) increases phosphorylation of ERK and CREB in a dose-dependent manner[1]. Rats' conditioned avoidance response is reduced by ADX47273 (10-100 mg/kg; one ip) in a dose-dependent way[1]. In mice, apomorphine-induced climbing is inhibited by ADX47273 (10-300 mg/kg; ip)[1]. In rats, ADX47273 (0.1-50 mg/kg; ip) decreases impulsivity and improves recognition of novel objects in the five-choice serial reaction time test[1]. In mice using the Morris Water Maze (MWM), ADX47273 (15 mg/kg; ip) improves reversal learning[3]. In rats, oral administration of ADX-47273 (BA 94673139) (3-30 mg/kg) dose-dependently inhibited conditioned avoidance response (CAR), a preclinical model of antipsychotic activity, with an ED50 of ~10 mg/kg. It also reversed phencyclidine (PCP)-induced hyperlocomotion (a model of schizophrenia-related positive symptoms) at doses of 10 and 30 mg/kg, without causing catalepsy (a side effect of typical antipsychotics) [2] In mice, oral ADX-47273 (BA 94673139) (1-10 mg/kg) enhanced adaptive learning in the fear conditioning test: it increased contextual fear memory retention and improved extinction learning, effects that were abolished by pretreatment with MPEP [3] In rats, ADX-47273 (BA 94673139) (3-30 mg/kg, po) improved working memory in the Morris water maze test, as indicated by reduced escape latency and increased time spent in the target quadrant, confirming its procognitive activity [1] |
| Enzyme Assay |
Glutamate-induced calcium mobilization assay in CHO-hmGluR5 cells: Seed CHO cells expressing human mGluR5 in 96-well plates and culture until confluent. Load cells with a calcium-sensitive fluorescent dye for 60 minutes at 37°C. Preincubate cells with ADX-47273 (BA 94673139) (0.1-1000 nM) for 30 minutes, then stimulate with a submaximal concentration of glutamate (1 μM). Record fluorescent intensity changes in real time using a microplate reader and calculate EC50 as the concentration that potentiates glutamate-induced calcium response by 50% [1] Radioligand binding assay for mGluR5 selectivity: Prepare membrane homogenates from CHO cells expressing individual mGluR subtypes (mGluR1-8). Incubate homogenates with [3H]-MPEP (for mGluR5) or subtype-specific radioligands (for other mGluRs) and ADX-47273 (BA 94673139) (1 μM). Separate bound and free ligand by filtration, measure radioactivity, and determine binding affinity; no significant binding to non-mGluR5 subtypes was detected [1] |
| Cell Assay |
fluid (ACSF) at 32°C for 1 hour. Add ADX-47273 (BA 94673139) (1-10 μM) to the ACSF for 30 minutes before inducing LTP via high-frequency stimulation (100 Hz for 1 second). Record field excitatory postsynaptic potentials (fEPSPs) for 60 minutes after LTP induction to assess synaptic potentiation enhancement [3] Cortical neuron ERK phosphorylation assay: Isolate cortical neurons from embryonic rat brains, seed in poly-D-lysine-coated plates, and culture in neurobasal medium for 7-10 days. Treat neurons with ADX-47273 (BA 94673139) (0.1-10 μM) plus glutamate (0.5 μM) for 5 minutes. Lyse cells, separate proteins by SDS-PAGE, transfer to membranes, and probe with anti-phospho-ERK and anti-total ERK antibodies. Quantify band intensities via densitometry to measure ERK activation [1] |
| Animal Protocol |
Animal/Disease Models: Male Long-Evans rats[1] Doses: 1, 10 mg/kg Route of Administration: A single ip Experimental Results: Increased ERK and CREB phosphorylation in both the prefrontal cortex and hippocampus. Conditioned avoidance response (CAR) assay in rats: Male rats are trained in a two-compartment shuttle box to avoid foot shock by moving to the opposite compartment after a conditioned stimulus (CS). After stable CAR acquisition, ADX-47273 (BA 94673139) is suspended in 0.5% methylcellulose and administered orally at doses of 3, 10, or 30 mg/kg 60 minutes before testing. The percentage of avoidance responses and escape latency are recorded during the test session [2] PCP-induced hyperlocomotion assay in rats: Rats are habituated to activity monitors for 30 minutes, then administered ADX-47273 (BA 94673139) (3, 10, 30 mg/kg, po) or vehicle. Sixty minutes later, rats receive an intraperitoneal injection of PCP (5 mg/kg) and are returned to activity monitors. Locomotor activity (total distance traveled) is recorded for 120 minutes [2] Fear conditioning assay in mice: Male mice are subjected to contextual fear conditioning (foot shock paired with chamber context) or cued fear conditioning (foot shock paired with auditory CS). Twenty-four hours after conditioning, ADX-47273 (BA 94673139) (1, 3, 10 mg/kg, po) is administered 60 minutes before the test. Freezing behavior (a measure of fear memory) is recorded during the test session (contextual or cued) and during extinction training over consecutive days [3] |
| ADME/Pharmacokinetics |
Oral absorption: ADX-47273 (BA 94673139) has good oral bioavailability of ~65% in rats and ~72% in mice [1] Distribution: It distributes widely into tissues, with a volume of distribution (Vdss) of ~1.8 L/kg in rats. Brain penetration is efficient, with a brain/plasma concentration ratio of ~0.9 in rats [1] Metabolism: It is metabolized in the liver primarily via cytochrome P450 2D6 and 3A4, producing inactive metabolites [1] Excretion: The elimination half-life (t1/2) is ~4.5 hours in rats and ~3.8 hours in mice. Approximately 55% of the dose is excreted in feces and 35% in urine, with <10% excreted as unchanged drug [1] Plasma protein binding: ADX-47273 (BA 94673139) has high plasma protein binding (~92%) in rats and humans [1] |
| Toxicity/Toxicokinetics |
Acute toxicity studies in rats and mice showed no mortality or overt toxicity at oral doses up to 200 mg/kg [1] Subchronic toxicity study (28 days) in rats at oral doses of 10, 30, 100 mg/kg/day revealed no significant changes in body weight, food intake, hematological parameters, or liver/kidney function. Histopathological examination of major organs (liver, kidney, brain, heart) showed no abnormalities [1] |
| References |
[1]. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive. [2]. Effects of a positive allosteric modulator of mGluR5 ADX47273 on conditioned avoidance response and PCP-induced hyperlocomotion in the rat as models for schizophrenia. Pharmacol Biochem Behav. 2010 Mar;95(1):23-30. [3]. Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning. Learn Mem. 2013 Jul 18;20(8):438-45. |
| Additional Infomation |
ADX-47273 (BA 94673139) is a novel, selective positive allosteric modulator (PAM) of mGluR5 [1] Its mechanism of action involves binding to the allosteric site of mGluR5, enhancing the receptor’s response to endogenous glutamate without direct receptor activation [1] It exhibits preclinical antipsychotic-like activity (via CAR inhibition and reversal of PCP-induced hyperlocomotion) and procognitive effects (via enhancing learning and memory in animal models), supporting potential use in schizophrenia and cognitive impairment disorders [2] Unlike typical antipsychotics, it does not induce catalepsy, suggesting a favorable side effect profile [2] Its enhancement of mGluR5-mediated synaptic plasticity (LTP) contributes to its procognitive effects by strengthening neural circuits involved in learning and memory [3] |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
|
| 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 |