VU0364572 (trifluoroacetate salt)

VU0364572 is a potent and selective agonist of the muscarinic acetylcholine receptor 1 (M₁; EC₅₀ = 0.2 mM compared to >10 mM for M₂-M₅).¹ It induces concentration-dependent increases in Ca²⁺ mobilization and ERK1/2 phosphorylation in CHO cells transfected with the human M₁ receptor (EC₅₀s = 0.89 and 10 mM, respectively) with no effect on β-arrestin recruitment. VU0364572 also improves hippocampal-dependent spatial learning and localization abilities and acquistion of contextual fear learning but cannot reverse amphetamine-induced hyperlocomotion in rats. This suggests therapeutic potential of VU0364572 for the treatment of Alzheimer's disease but not psychosis.²

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1. Lebois, E.P., Digby, G.J., Sheffler, D.J., et al. Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071. Bioorg. Med. Chem. Lett. 21(21), 6451-6455 (2011).

2. Digby, G.J., Noetzel, M.J., Bubser, M., et al. Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models. J. Neurosci. 32(25), 8532-8544 (2012).