| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 50mg |
|
||
| Other Sizes |
|
| Targets |
5-HT1A Receptor
|
|---|---|
| ln Vitro |
F13640 (befiradol) is a novel 5-HT(1A) receptor agonist with exceptional selectivity vs. other receptors and binding sites[1]. F13640 activates both 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) receptors in prefrontal cortex with a similar potency. Both activities are likely involved in the analgesic properties of the compound.
|
| ln Vivo |
F13640 reduced the activity of dorsal raphe serotonergic neurons at 0.2-18.2 μg kg(-1), i.v. (cumulative doses; ED(50) = 0.69 μg kg(-1), i.v.) and increased the discharge rate of 80% of mPFC pyramidal neurons in the same dose range (ED(50) = 0.62 μg kg(-1), i.v.). Both effects were reversed by the subsequent administration of the 5-HT(1A) receptor antagonist (±)WAY100635. In microdialysis studies, F13640 (0.04-0.63 mg kg(-1), i.p.) dose-dependently decreased extracellular 5-HT in the hippocampus and mPFC. Likewise, F13640 (0.01-2.5 mg kg(-1), i.p.) dose-dependently increased extracellular DA in mPFC, an effect dependent on the activation of postsynaptic 5-HT(1A) receptors in mPFC. Local perfusion of F13640 in mPFC (1-1,000 μM) also increased extracellular DA in a concentration-dependent manner. Both the systemic and local effects of F13640 were prevented by prior (±)WAY100635 administration[1].
|
| Animal Protocol |
Rats were anaesthetized with chloral hydrate (400–500 mg kg−1, i.p.) or isoflurane. A guide cannula with a dummy probe was stereotaxically implanted into the mPFC, stereotaxic coordinates: AP +3.0 mm, L +0.8 mm, DV −1.7 mm, or the hippocampus: AP −4.8 mm, L +4.6 mm, DV −4.6 mm, from bregma and skull surface. Following surgery and recovery from anesthesia, animals were returned to their home cages. At the end of the day, each rat was placed in a microdialysis cage. On the following day, the dummy probe was replaced by a microdialysis probe (3 mm length, 0.5 mm diameter; CMA, Microdialysis AB). The probe was continuously perfused (1.1 μl min−1) with artificial CSF (aCSF) containing 1 μM citalopram for the measure of 5-HT. At least 2 h after probe insertion, samples were collected every 20 min with the first four samples used for baseline. For the experiment with systemic administration of the compounds, saline or (±)WAY100635 were injected s.c., followed, 40 min later, by i.p. administration of saline or F13640. For the experiments with local perfusion, saline was injected s.c. and 40 min later, F13640 was added to the perfusion medium for the concentration–response experiment. For the antagonism, (±)WAY100635 (or aCSF) was delivered through the dialysis probe and 40 min later, F13640 was added to the perfusion medium. Samples were collected for 140 min after administration or beginning of the perfusion of the agonist. At the end of the experiment, rats were killed by anesthetic overdose (pentobarbital 160 mg kg−1, i.p.) and the brain was removed, frozen and cut in a cryomicrotome (Jung Frigocut 2800) to verify the placement of the probe.[1]
|
| ADME/Pharmacokinetics |
NLX-112 (i.e., F13640, befiradol) exhibits nanomolar affinity, exceptional selectivity and full agonist efficacy at serotonin 5-HT1A receptors. NLX-112 shows efficacy in rat, marmoset and macaque models of L-DOPA induced dyskinesia (LID) in Parkinson's disease and has shown clinical efficacy in a Phase 2a proof-of-concept study for this indication. Here we investigated, in rats, its pharmacodynamic, pharmacokinetic (PK) and brain 5-HT1A receptor occupancy profiles, and its PK properties in the absence and presence of L-DOPA. Total and free NLX-112 exposure in plasma, CSF and striatal ECF was dose-proportional over the range tested (0.04, 0.16 and 0.63 mg/kg i.p.). NLX-112 exposure increased rapidly (Tmax 0.25-0.5h) and exhibited approximately threefold longer half-life in brain than in plasma (1.1 and 3.6h, respectively). At a pharmacologically relevant dose of 0.16 mg/kg i.p., previously shown to elicit anti-LID activity in parkinsonian rats, brain concentration of NLX-112 was 51-63 ng/g from 0.15 to 1h. In microPET imaging experiments, NLX-112 showed dose-dependent reduction of 18F-F13640 (i.e., 18F-NLX-112) brain 5-HT1A receptor labeling in cingulate cortex and striatum, regions associated with motor control and mood, with almost complete inhibition of labeling at the dose of 0.63 mg/kg i.p.. Co-administration of L-DOPA (6 mg/kg s.c., a dose used to elicit LID in parkinsonian rats) together with NLX-112 (0.16 mg/kg i.p.) did not modify PK parameters in rat plasma and brain of either NLX-112 or L-DOPA. Here, we demonstrate that NLX-112's profile is compatible with 'druggable' parameters for CNS indications, and the results provide measures of brain concentrations and 5-HT1A receptor binding parameters relevant to the anti-dyskinetic activity of the compound.https://pubmed.ncbi.nlm.nih.gov/39096379/
|
| References | |
| Additional Infomation |
Serotonin 5-HT1 Receptor Agonists
Endogenous compounds and drugs that specifically stimulate SEROTONIN 5-HT1 RECEPTORS. Included under this heading are agonists for one or more of the specific 5-HT1 receptor subtypes.
Rationale: F13640 (befiradol) is a novel 5-HT(1A) receptor agonist with exceptional selectivity vs. other receptors and binding sites. It shows analgesic activity in animal models and is currently developed for human use. Objectives: Given the potential dual role of the serotonergic system in pain, through the modulation of ascending signals in spinal cord and their emotional processing by corticolimbic areas, we examined the in vivo activity of F13640 at somatodendritic autoreceptors and postsynaptic 5-HT(1A) heteroreceptors in medial prefrontal cortex (mPFC). Methods: In vivo single unit recordings and intracerebral microdialysis in the rat. Results: F13640 reduced the activity of dorsal raphe serotonergic neurons at 0.2-18.2 μg kg(-1), i.v. (cumulative doses; ED(50) = 0.69 μg kg(-1), i.v.) and increased the discharge rate of 80% of mPFC pyramidal neurons in the same dose range (ED(50) = 0.62 μg kg(-1), i.v.). Both effects were reversed by the subsequent administration of the 5-HT(1A) receptor antagonist (±)WAY100635. In microdialysis studies, F13640 (0.04-0.63 mg kg(-1), i.p.) dose-dependently decreased extracellular 5-HT in the hippocampus and mPFC. Likewise, F13640 (0.01-2.5 mg kg(-1), i.p.) dose-dependently increased extracellular DA in mPFC, an effect dependent on the activation of postsynaptic 5-HT(1A) receptors in mPFC. Local perfusion of F13640 in mPFC (1-1,000 μM) also increased extracellular DA in a concentration-dependent manner. Both the systemic and local effects of F13640 were prevented by prior (±)WAY100635 administration. Conclusions: These results indicate that, upon systemic administration, F13640 activates both 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) receptors in prefrontal cortex with a similar potency. Both activities are likely involved in the analgesic properties of the compound.[1] |
| Molecular Formula |
C20H22CLF2N3O
|
|---|---|
| Molecular Weight |
393.86
|
| Exact Mass |
393.142
|
| Elemental Analysis |
C, 60.99; H, 5.63; Cl, 9.00; F, 9.65; N, 10.67; O, 4.06
|
| CAS # |
208110-64-9
|
| Related CAS # |
Befiradol hydrochloride;2436760-81-3
|
| PubChem CID |
9865384
|
| Appearance |
Typically exists as white to off-white solids at room temperature
|
| Density |
1.3
|
| LogP |
4.245
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
27
|
| Complexity |
502
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O=C(C1=CC=C(F)C(Cl)=C1)N2CCC(CNCC3=NC=C(C)C=C3)(F)CC2
|
| InChi Key |
PKZXLMVXBZICTF-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C20H22ClF2N3O/c1-14-2-4-16(25-11-14)12-24-13-20(23)6-8-26(9-7-20)19(27)15-3-5-18(22)17(21)10-15/h2-5,10-11,24H,6-9,12-13H2,1H3
|
| Chemical Name |
(3-chloro-4-fluorophenyl)-[4-fluoro-4-[[(5-methylpyridin-2-yl)methylamino]methyl]piperidin-1-yl]methanone
|
| Synonyms |
F-13640; F 13640; NLX-112; Befiradol (free base); Befiradol [INN]; RAT9OHA1YH; F13640; CHEMBL45305;F13640
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~102 mg/mL (~258.98 mM)
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5390 mL | 12.6949 mL | 25.3897 mL | |
| 5 mM | 0.5078 mL | 2.5390 mL | 5.0779 mL | |
| 10 mM | 0.2539 mL | 1.2695 mL | 2.5390 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03347331 | COMPLETED | Drug: [18F]F13640 Drug: [18F]F13640 |
Healthy Subjects Neurological Pathology |
Hospices Civils de Lyon | 2018-04-23 | Early Phase 1 |
| NCT05148884 | COMPLETEDWITH RESULTS | Drug: NLX-112 Drug: Placebo |
Medication-Induced Dyskinesia | Neurolixis SAS | 2021-11-09 | Phase 2 |
| NCT05084469 | UNKNOWN STATUS | Procedure: PET-MRI in pain-free remission period | Cluster Headache, Episodic | Hospices Civils de Lyon | 2021-11-01 |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
