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 µM. 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

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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 rodents. ACS 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 mice. Proc. Natl. Acad. Sci. USA 112(45), 14078-14083 (2015).