title: Diverse Effects on M1Signaling and Adverse Effect Liability within a Series of M1Ago-PAMs.
abstract: Both historical clinical and recent preclinical data suggest that the M1muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer's disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M1activation. Efforts then shifted to focus on selective activation of M1via either allosteric agonists or positive allosteric modulators (PAMs). While M1PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility. Here, we report studies aimed at understanding the subtle structural and pharmacological nuances that differentiate efficacy from adverse effect liability within an indole-based series of M1ago-PAMs. Our data demonstrate that closely related M1PAMs can display striking differences in their in vivo activities, especially their propensities to induce adverse effects. We report the discovery of a novel PAM in this series that is devoid of observable adverse effect liability. Interestingly, the molecular pharmacology profile of this novel PAM is similar to that of a representative M1PAM that induces severe AEs. For instance, both compounds are potent ago-PAMs that demonstrate significant interaction with the orthosteric site (either bitopic or negative cooperativity). However, there are subtle differences in efficacies of the compounds at potentiating M1responses, agonist potencies, and abilities to induce receptor internalization. While these differences may contribute to the differential in vivo profiles of these compounds, the in vitro differences are relatively subtle and highlight the complexities of allosteric modulators and the need to focus on in vivo phenotypic screening to identify safe and effective M1PAMs.
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Jerri M
authors.initials: JM
authors.lastname: Rook
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Masahito
authors.initials: M
authors.lastname: Abe
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Kellie D
authors.initials: KD
authors.lastname: Nance
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Vincent B
authors.initials: VB
authors.lastname: Luscombe
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Adams
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Dickerson
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Remke
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Garcia-Barrantes
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Engers
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Sichen
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Jarrett J
authors.initials: JJ
authors.lastname: Foster
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Pharmacology, ‡Department of Chemistry, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States.
authors.forename: Craig W
authors.identifier: 0000-0003-0168-1445
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1
keywords: M1; ago-PAM; agonist; muscarinic acetylcholine receptor; positive allosteric modulator (PAM); seizure