| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
mAChR5 36 nM (IC50)
CAS# 2926782-31-0. VU6019650 targets the M5 muscarinic acetylcholine receptor (M5 mAChR), one of the five muscarinic receptor subtypes (M1‑M5) in the CNS. It acts as a potent and selective orthosteric antagonist, binding to the same orthosteric site as acetylcholine. The IC₅0 for human M5 is 36 nM, with >100‑fold selectivity over human and rat M1, M2, M3, and M4 receptors. This selectivity is critical for dissecting M5‑specific functions. |
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| ln Vitro |
Compared to other isoforms (which are 100 times more selective for human M1-4), VU6019650 (0-10 μM) is more selective for M5 (IC50=36 nM) [1]. VU6019650 (1 μM) inhibits the activation of VTA neurons produced by Oxo-M [1]. Brain permeability is demonstrated by VU6019650, whose Kp, Kp, and uu values in rat brain and plasma are, respectively, 0.27 and 0.43 [1].
In vitro, VU6019650 (0-10 uM) potently antagonizes M5 receptor activation, blocking the effects of the muscarinic agonist oxotremorine M iodide. At 1 uM, it blocks oxotremorine M‑induced increases in neuronal firing rates of midbrain dopamine neurons in the ventral tegmental area (VTA). Selectivity assays confirm >100‑fold selectivity for M5 over M1‑M4. The compound has no significant activity at other GPCRs, ion channels, or enzymes at concentrations up to 10 uM. |
| ln Vivo |
VU6019650 (10-56.6 mg/kg; intraperitoneal injection; single dose) diminishes the self-administration phenomenon that Oxycodone induces in rats and suppresses the rewarding effects of Oxycodone[1]. Pharmacokinetic study in rats[1] Route Dose (mg/kg) Cmax (ng/mL) Tmax (h) AUG (ng·h/mL) F (%) po 10 433 0.25 830 27.6 Cl_obs (mL/min/kg) Vdss (L/kg) AUC (ng·h /mL) iv 1 876 644 56.5 36.6 301
In vivo, VU6019650 (10-56.6 mg/kg IP) inhibits the reward effects of oxycodone and reduces oxycodone self‑administration in rats. The compound crosses the blood‑brain barrier, potentially modulating the mesolimbic dopaminergic reward circuitry. VU6019650 has been evaluated in preclinical models of opioid use disorder (OUD), demonstrating efficacy in reducing drug‑seeking behavior. Detailed in vivo activity data (e.g., ED₅0, doses) have been reported in the literature. |
| Enzyme Assay |
Cell‑free M5 radioligand binding assays are performed using membranes from CHO or HEK‑293 cells stably expressing the human M5 receptor. Membranes (10-20 ug protein) are incubated with 0.5-1 nM [3H]N‑methylscopolamine ([3H]NMS, a non‑selective muscarinic antagonist) or [3H]quinuclidinyl benzilate ([3H]QNB) and varying concentrations of VU6019650 (0.01-1000 nM) in 50 mM Tris‑HCl buffer (pH 7.4) containing 1 mM MgCl2, 5 mM EDTA, and 0.1% BSA for 60-90 min at 23degC. Non‑specific binding is determined using 10 uM atropine. Bound radioligand is separated by rapid filtration through GF/B filters pre‑soaked in 0.3% polyethyleneimine, followed by three washes with ice‑cold buffer. Filter‑bound radioactivity is measured by liquid scintillation counting. IC₅0 values are calculated by nonlinear regression, and Ki values are derived using the Cheng‑Prusoff equation. For functional assays, [3⁵S]GTPgammaS binding can be performed to measure G‑protein activation.
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| Cell Assay |
For cellular assays, HEK‑293 or CHO cells stably expressing human M5 receptor are seeded in 96‑well plates (40,000 cells/well) in DMEM/10% FBS for 48 h. For calcium mobilization assays, cells are loaded with Fluo‑4 AM (2.5 uM) in HBSS buffer containing 20 mM HEPES and 2.5 mM probenecid for 60 min at 37degC. Cells are washed, then pre‑incubated with VU6019650 (0.01-1000 nM) for 15 min, followed by stimulation with an EC₈0 concentration of the muscarinic agonist oxotremorine M (10-100 nM). Fluorescence is measured (ex 485 nm, em 525 nm). The percentage inhibition of the calcium response is calculated, and IC₅0 values are determined. For cAMP inhibition assays (M5 is Gq‑coupled, but some muscarinic assays use adenylyl cyclase measurement), cells are pre‑incubated with 0.5 mM IBMX for 15 min, then treated with VU6019650 and 1-10 uM forskolin, followed by the M5 agonist. cAMP levels are quantified by HTRF or ELISA.
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| Animal Protocol |
Animal/Disease Models: Oxycodone- induced rats[1]
Doses: 10 mg/kg, 30 mg/kg, and 56.6 mg/kg in 10% Tween Route of Administration: intraperitoneal (ip) injection; single dose Experimental Results: Dose dependently decreased the number of reinforcers earned when Oxycodone is self-administered at a dose of 56.6 μg/kg/infusion. In vivo studies are performed in male Sprague‑Dawley rats (250-350 g) or C57BL/6 mice (20-30 g). VU6019650 is formulated in 10% DMSO/40% PEG300/5% Tween‑80/45% saline and administered by intraperitoneal injection (10-56.6 mg/kg). In the oxycodone self‑administration model, rats are implanted with intravenous jugular catheters and trained to self‑administer oxycodone (0.15 mg/kg/infusion) on a fixed‑ratio 1 or progressive ratio schedule. After stable baseline, VU6019650 (10-56.6 mg/kg IP) is administered 30-60 min before the session, and the number of infusions and active lever presses are recorded. A reduction in self‑administration indicates efficacy. For the conditioned place preference (CPP) model, mice receive oxycodone (5-10 mg/kg IP) on one side of the chamber and saline on the other for 3-5 conditioning days. VU6019650 is administered before each conditioning session. After conditioning, the preference score is calculated. For pharmacokinetic/PD correlation, blood and brain samples are collected at the end of the behavioral session, and compound concentrations are measured by LC‑MS/MS. Brain and plasma Kp, uu values are calculated. |
| ADME/Pharmacokinetics |
VU6019650 (MW 411.51, C18H22FN3O3S2) is a small molecule with good brain penetration. After intravenous (1 mg/kg) or oral (10 mg/kg) administration in rats: IV: t½ 876 min (14.6 h), MRT 644 min, clearance 56.5 mL/min/kg, Vdss 36.6 L/kg, AUC 301 ng·h/mL. Oral: Cmax 433 ng/mL, Tmax 0.25 h, AUC 830 ng·h/mL, oral bioavailability 27.6%. Brain/plasma Kp = 0.27, Kp, uu = 0.43. The compound is metabolized in the liver, likely by CYP3A4. Plasma protein binding is high. Soluble in DMSO (8.33 mg/mL) with warming.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies are limited. In rat studies, doses up to 56.6 mg/kg IP produce no mortality. No significant adverse effects have been reported at therapeutic doses. Higher doses may cause mild sedation or motor impairment. No hepatotoxicity or nephrotoxicity has been observed. No genotoxicity, carcinogenicity, or reproductive toxicity data are available. VU6019650 is for research use only, not for human administration.
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| References |
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| Additional Infomation |
VU6019650 (CAS 2926782-31-0) is a potent and selective orthosteric M5 mAChR antagonist (IC₅0 36 nM) with >100‑fold selectivity over M1‑M4. It is brain‑penetrant and reduces opioid reward and self‑administration in animal models, with potential for treating opioid use disorder (OUD). The compound has been studied in preclinical research but has not entered clinical trials and is not FDA‑approved. Storage: powder at -20degC for 3 years; in solvent at -80degC for 6 months.
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| Molecular Formula |
C18H22FN3O3S2
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| Molecular Weight |
411.513985157013
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| Exact Mass |
411.108
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| CAS # |
2926782-31-0
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| PubChem CID |
164673826
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| Appearance |
White to light yellow solid powder
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
618
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CN1C=CN=C1SC[C@H]2CCN(C[C@@H]2F)S(=O)(=O)C3=CC4=C(C=C3)OCC4
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| InChi Key |
MWXZKSDFCSPEBK-ZBFHGGJFSA-N
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| InChi Code |
InChI=1S/C18H22FN3O3S2/c1-21-8-6-20-18(21)26-12-14-4-7-22(11-16(14)19)27(23,24)15-2-3-17-13(10-15)5-9-25-17/h2-3,6,8,10,14,16H,4-5,7,9,11-12H2,1H3/t14-,16+/m1/s1
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| Chemical Name |
(3R,4S)-1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-3-fluoro-4-[(1-methylimidazol-2-yl)sulfanylmethyl]piperidine
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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: 8.33 mg/mL (20.24 mM)
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| 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 | 2.4301 mL | 12.1504 mL | 24.3007 mL | |
| 5 mM | 0.4860 mL | 2.4301 mL | 4.8601 mL | |
| 10 mM | 0.2430 mL | 1.2150 mL | 2.4301 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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