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Research ArticleDrug Discovery and Translational Medicine

Evidence for Classical Cholinergic Toxicity Associated with Selective Activation of M1 Muscarinic Receptors

Andrew Alt, Annapurna Pendri, Robert L. Bertekap Jr., Guo Li, Yulia Benitex, Michelle Nophsker, Kristin L. Rockwell, Neil T. Burford, Chi Shing Sum, Jing Chen, John J. Herbst, Meredith Ferrante, Adam Hendricson, Mary Ellen Cvijic, Ryan S. Westphal, Jonathan O’Connell, Martyn Banks, Litao Zhang, Robert G. Gentles, Susan Jenkins, James Loy and John E. Macor
Journal of Pharmacology and Experimental Therapeutics February 2016, 356 (2) 293-304; DOI: https://doi.org/10.1124/jpet.115.226910
Andrew Alt
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Annapurna Pendri
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Robert L. Bertekap Jr.
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Guo Li
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Yulia Benitex
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Michelle Nophsker
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Kristin L. Rockwell
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Neil T. Burford
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Chi Shing Sum
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Jing Chen
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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John J. Herbst
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Meredith Ferrante
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Adam Hendricson
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Mary Ellen Cvijic
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Ryan S. Westphal
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Jonathan O’Connell
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Martyn Banks
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Litao Zhang
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Robert G. Gentles
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Susan Jenkins
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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James Loy
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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John E. Macor
Research and Development/Discovery, Bristol-Myers Squibb Company, Wallingford, Connecticut (A.A., A.P., R.L.B., G.L., Y.B., M.N., K.L.R, N.T.B., J.J.H., M.F., A.H., R.S.W., J.O., M.B., R.G., S.J., J.L.); Research and Development/Discovery, Bristol-Myers Squibb Company, Hopewell, New Jersey (C.S.S., M.E.C.); and Research and Development/Discovery, Bristol-Myers Squibb Company, Lawrence Township, New Jersey (J.C., L.Z., J.E.M.)
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Abstract

The muscarinic acetylcholine receptor subtype 1 (M1) receptors play an important role in cognition and memory, and are considered to be attractive targets for the development of novel medications to treat cognitive impairments seen in schizophrenia and Alzheimer’s disease. Indeed, the M1 agonist xanomeline has been shown to produce beneficial cognitive effects in both Alzheimer’s disease and schizophrenia patients. Unfortunately, the therapeutic utility of xanomeline was limited by cholinergic side effects (sweating, salivation, gastrointestinal distress), which are believed to result from nonselective activation of other muscarinic receptor subtypes such as M2 and M3. Therefore, drug discovery efforts targeting the M1 receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M1 receptor ligands have been described, which exhibit excellent selectivity for M1 over other muscarinic receptor subtypes. In the current study, the following three compounds with mixed agonist/positive allosteric modulator activities that are highly functionally selective for the M1 receptor were tested in rats, dogs, and cynomologous monkeys: (3-((1S,2S)-2-hydrocyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one; 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; and (R)-ethyl 3-(2-methylbenzamido)-[1,4′-bipiperidine]-1′-carboxylate). Despite their selectivity for the M1 receptor, all three compounds elicited cholinergic side effects such as salivation, diarrhea, and emesis. These effects could not be explained by activity at other muscarinic receptor subtypes, or by activity at other receptors tested. Together, these results suggest that activation of M1 receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M1 receptor–targeted therapeutics since it suggests that dose-limiting cholinergic side effects still reside in M1 receptor selective activators.

Footnotes

    • Received June 19, 2015.
    • Accepted November 17, 2015.
  • dx.doi.org/10.1124/jpet.115.226910.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 356 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 356, Issue 2
1 Feb 2016
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Research ArticleDrug Discovery and Translational Medicine

Cholinergic Toxicity Produced by Selective M1 Activation

Andrew Alt, Annapurna Pendri, Robert L. Bertekap, Guo Li, Yulia Benitex, Michelle Nophsker, Kristin L. Rockwell, Neil T. Burford, Chi Shing Sum, Jing Chen, John J. Herbst, Meredith Ferrante, Adam Hendricson, Mary Ellen Cvijic, Ryan S. Westphal, Jonathan O’Connell, Martyn Banks, Litao Zhang, Robert G. Gentles, Susan Jenkins, James Loy and John E. Macor
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 293-304; DOI: https://doi.org/10.1124/jpet.115.226910

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Research ArticleDrug Discovery and Translational Medicine

Cholinergic Toxicity Produced by Selective M1 Activation

Andrew Alt, Annapurna Pendri, Robert L. Bertekap, Guo Li, Yulia Benitex, Michelle Nophsker, Kristin L. Rockwell, Neil T. Burford, Chi Shing Sum, Jing Chen, John J. Herbst, Meredith Ferrante, Adam Hendricson, Mary Ellen Cvijic, Ryan S. Westphal, Jonathan O’Connell, Martyn Banks, Litao Zhang, Robert G. Gentles, Susan Jenkins, James Loy and John E. Macor
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 293-304; DOI: https://doi.org/10.1124/jpet.115.226910
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