VU0119498

VU0119498 is a positive allosteric modulator (PAM) of M₁, M₃, and M₅ muscarinic acetylcholine receptors (mAChRs; EC₅₀s = 6.04, 6.38, and 4.08 µM, respectively, in calcium mobilization assays).¹ It is selective for M₁, M₃, and M₅ mAChRs over M₂ and M₄ mAChRs in CHO cells expressing the human receptors. VU0119498 (20 µM) enhances ACh-induced insulin secretion in MIN6-K8 pancreatic β-cells.² It decreases glucose tolerance and increases insulin secretion in mice fed normal chow, as well as in a mouse model of high-fat diet-induced obesity, when administered at a dose of 0.5 mg/kg.

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1. Bridges, T.M., Marlo, J.E., Niswender, C.M., et al. Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. J. Med. Chem. 52(11), 3445-3448 (2009).

2. Zhu, L., Rossi, M., Cohen, A., et al. Allosteric modulation of β-cell M3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice. Proc. Natl. Acad. Sci. U.S.A. 116(37), 18684-18690 (2019).