VU0255035

VU0255035 is a competitive, orthosteric antagonist of the muscarinic M₁ receptor (IC₅₀ = 130 nM).^1,2 It displays at least 75-fold selectivity for M₁ over other muscarinic receptors, as well as a panel of receptors, ion channels, and transporters.^1,2 VU0255035 is effective in cells and in vivo and brain penetrating, blocking pilocarpine-induced seizures without disrupting contextual fear conditioning in mice.^1,2 VU0255035 is used to examine the role of the M₁ receptor in diverse situations.^3,4,5

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1. Sheffler, D.J., Williams, R., Bridges, T.M., et al. A novel selective muscarinic acetylcholine receptor subtype 1 antagonist reduces seizures without impairing hippocampus-dependent learning. Mol. Pharmacol. 76(2), 356-368 (2009).

2. Weaver, C.D., Sheffler, D.J., Lewis, L.M., et al. Discovery and development of a potent and highly selective small molecule muscarinic acetylcholine receptor subtype I (mAChR 1 or M1) antagonist in vitro and in vivo probe. Curr. Top. Med. Chem. 9(13), 1217-1226 (2009).

3. Shirey, J.K., Brady, A.E., Jones, P.J., et al. A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. J. Neurosci. 29(45), 14271-14286 (2009).

4. Xiang, Z., Thompson, A.D., Jones, C.K., et al. Roles of the M1 muscarinic acetylcholine receptor subtype in the regulation of basal ganglia function and implications for the treatment of Parkinson’s disease. J. Pharmacol. Exp. Ther. 340(3), 595-603 (2012).

5. Harada, K., Matsuoka, H., Miyata, H., et al. Identification of muscarinic receptor subtypes involved in catecholamine secretion in adrenal medullary chromaffin cells by genetic deletion. Br. J. Pharmacol. 172(5), 1348-1359 (2015).