VU6019650

• CAT Number: I042369
• CAS Number: 2926782-31-0
• Molecular Formula: C18H22FN3O3S2
• Molecular Weight: 411.51
• Purity: ≥95%
• Synonyms: (3R,4S)-1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-3-fluoro-4-[(1-methylimidazol-2-yl)sulfanylmethyl]piperidine
• InChI: 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
• InChIKey: MWXZKSDFCSPEBK-ZBFHGGJFSA-N
• SMILES: CN1C=CN=C1SCC2CCN(CC2F)S(=O)(=O)C3=CC4=C(C=C3)OCC4

VU6019650 is a potent and selective orthosteric antagonist of M5 mAChR (IC50=36 nM), can be used for opioid use disorder (OUD) relief. VU6019650 can cross blood brain barrier, potentially modulates the mesolimbic dopaminergic reward circuitry. VU6019650 blocks Oxotremorine M iodide (HY-101372A) induced increases of neuronal firing rates of midbrain dopamine neurons in the ventral tegmental area (VTA)[1][2].
VU6019650 (0-10 μM) shows high selectivity for M5 (IC50=36 nM) over other subtypes (>100-fold selectivity against human M1-4)[1].
VU6019650 (1 μM) blocks Oxo-M-induced activation of VTA neurons[1].
VU6019650 exhibits brain penetrance with rat brain and plasma Kp, Kp, uu values of 0.27 and 0.43, respectively[1].
VU6019650 (10-56.6 mg/kg; i.p.; single dose) inhibits the rewarding effects of Oxycodone and reduces oxycodone self-administration in rats[1].

Pharmacokinetic Analysis in rats[1]

Route
Dose (mg/kg)
t(term) (min)
MRT (min)
Cl_obs (mL/min/kg)
Vdss(L/kg)
AUC (ng·h/mL)

i.v.
1
876
644
56.5
36.6
301

Route
Dose (mg/kg)
Cmax (ng/mL)
Tmax (h)
AUG (ng·h/mL)
F (%)

p.o.
10
433
0.25
830
27.6

Reference

[1]. Garrison AT, et al. 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.
 [Content Brief]

[2]. Capstick RA, et al. 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.
 [Content Brief]