VU6019650 is a potent and specific positive M5 mAChR antagonist (IC50=36 nM) that may be utilized in studies to alleviate opioid use disorder (OUD). VU6019650 is BBB (blood-brain barrier) penetrating and may modulate mesolimbic dopaminergic reward circuitry. VU6019650 blocks the Oxotremorine M iodide-induced increase in the firing rate of ventral tegmental area midbrain (VTA) dopamine neurons.

Physicochemical Properties

Molecular Formula	C18H22FN3O3S2
Molecular Weight	411.513985157013
Exact Mass	411.108
CAS #	2926782-31-0
PubChem CID	164673826
Appearance	White to light yellow solid powder
LogP	2.5
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	5
Heavy Atom Count	27
Complexity	618
Defined Atom Stereocenter Count	2
SMILES	CN1C=CN=C1SC[C@H]2CCN(C[C@@H]2F)S(=O)(=O)C3=CC4=C(C=C3)OCC4
InChi Key	MWXZKSDFCSPEBK-ZBFHGGJFSA-N
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
Chemical Name	(3R,4S)-1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-3-fluoro-4-[(1-methylimidazol-2-yl)sulfanylmethyl]piperidine
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	mAChR5 36 nM (IC50)
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].
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
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.
References	[1]. Development of VU6019650: A Potent, Highly Selective, and Systemically Active Orthosteric Antagonist of the M5 Muscarinic Acetylcholine Receptor for the Treatment of Opioid Use Disorder. J Med Chem. 2022 Apr 28;65(8):6273-6286. [2]. Discovery of a potent M5 antagonist with improved clearance profile. Part 1: Piperidine amide-based antagonists. Bioorg Med Chem Lett. 2022 Nov 15;76:128988.

Solubility Data

Solubility (In Vitro)

DMSO: 8.33 mg/mL (20.24 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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (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.