title: Evidence for Classical Cholinergic Toxicity Associated with Selective Activation of M1 Muscarinic Receptors.
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.
authors.affiliation: 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.) andrew.alt@bms.com.
authors.forename: Andrew
authors.initials: A
authors.lastname: Alt
authors.affiliation: 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.).
authors.forename: Annapurna
authors.initials: A
authors.lastname: Pendri
authors.affiliation: 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.).
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bertekap
authors.affiliation: 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.).
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.affiliation: 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.).
authors.forename: Yulia
authors.initials: Y
authors.lastname: Benitex
authors.affiliation: 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.).
authors.forename: Michelle
authors.initials: M
authors.lastname: Nophsker
authors.affiliation: 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.).
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Rockwell
authors.affiliation: 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.).
authors.forename: Neil T
authors.initials: NT
authors.lastname: Burford
authors.affiliation: 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.).
authors.forename: Chi Shing
authors.initials: CS
authors.lastname: Sum
authors.affiliation: 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.).
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.).
authors.forename: John J
authors.initials: JJ
authors.lastname: Herbst
authors.affiliation: 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.).
authors.forename: Meredith
authors.initials: M
authors.lastname: Ferrante
authors.affiliation: 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.).
authors.forename: Adam
authors.initials: A
authors.lastname: Hendricson
authors.affiliation: 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.).
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.affiliation: 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.).
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Westphal
authors.affiliation: 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.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: O'Connell
authors.affiliation: 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.).
authors.forename: Martyn
authors.initials: M
authors.lastname: Banks
authors.affiliation: 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.).
authors.forename: Litao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gentles
authors.affiliation: 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.).
authors.forename: Susan
authors.initials: S
authors.lastname: Jenkins
authors.affiliation: 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.).
authors.forename: James
authors.initials: J
authors.lastname: Loy
authors.affiliation: 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.).
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000378:metabolism*
chemical_list: D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1