Abstract
Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M4 allosteric potentiators. VU10010, the lead compound, potentiates the M4 response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M4 with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M4 knockout mice. Selective regulation of excitatory transmission by M4 suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.
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Acknowledgements
The authors thank K. Hemstapat, D.J. Sheffler, E.L. Days and N.T. Nalywajko for technical support and discussion of data. The authors also thank A. Levey (Emory University) for stable mAChR cell lines and T.I. Bonner (US National Institute of Mental Health) for the rM4 DNA construct. This work was supported by grants from the US National Institute of Mental Health and National Institute of Neurological Disorders and Stroke. Vanderbilt is a site in the US National Institutes of Health–supported Molecular Libraries Screening Center Network.
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J.K.S., cell-based and binding assays and handling of the manuscript; Z.X., electrophysiology; D.O. and R.W., chemical synthesis and chemical characterization; A.E.B., M4 cell line establishment; K.A.J. and C.M.N., human M4 data; J.E.A., electrophysiology; A.L.R., substructure search and chemical library selection; J.W., generated M4 knockout mice; D.W., analysis template design; P.J.C., principal investigator.
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Shirey, J., Xiang, Z., Orton, D. et al. An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission. Nat Chem Biol 4, 42–50 (2008). https://doi.org/10.1038/nchembio.2007.55
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DOI: https://doi.org/10.1038/nchembio.2007.55
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