VU0467154

VU0467154 is a positive allosteric modulator of the M₄ muscarinic acetylcholine receptor that potentiates acetylcholine responses in CHO cells expressing M₄ receptors (EC₅₀s = 17.7, 630, and 1,000 nM for rat, human, and cynomolgus monkey receptors, respectively).¹ It is selective for M₄ over M_1-3 and M₅ receptors and a panel of receptors, transporters, and cation channels when used at a concentration of 10 ?M. In vivo, VU0467154 (3-56.6 mg/kg, p.o.) reverses amphetamine-induced hyperlocomotion in rats. It reverses MK-801-induced hyperlocomotion, deficits in a pairwise visual discrimination task, and impairments in the acquisition of contextual fear conditioning in wild-type, but not M₄ knockout, mice. VU0467154 (3-30 mg/kg) also increases freezing behavior in contextual and tone fear conditioning tests in wild-type mice when administered prior to the conditioning session. Chronic administration of VU0467154 (10 mg/kg once daily) reduces motor incoordination and prevents decreases in locomotion in the YAC128 transgenic mouse model of Huntington's disease.²

1.Bubser, M., Bridges, T.M., Dencker, D., et al.Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodentsACS Chem. Neurosci.5(10)920-942(2014) 2.Pancani, T., Foster, D.J., Moehle, M.S., et al.Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 miceProc. Natl. Acad. Sci. USA112(45)14078-14083(2015)