An M1, M3, and M5 muscarinic receptor positive allosteric modulator
VU0119498 is a positive allosteric modulator (PAM) of M1, M3, and M5 muscarinic acetylcholine receptors (mAChRs; EC50s = 6.04, 6.38, and 4.08 ?M, 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 ?M) 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.
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 isatinsJ. 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 miceProc. Natl. Acad. Sci. U.S.A.116(37)18684-18690(2019)
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