Diverse Effects on M 1 Signaling and Adverse Effect Liability within a Series of M 1 Ago-PAMs.

Autor:	Rook JM; 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., Abe M; 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., Cho HP; 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., Nance KD; 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., Luscombe VB; 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., Adams JJ; 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., Dickerson JW; 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., Remke DH; 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., Garcia-Barrantes PM; 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., Engers DW; 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., Engers JL; 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., Chang S; 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., Foster JJ; 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., Blobaum AL; 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., Niswender CM; 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., Jones CK; 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., Conn PJ; 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., Lindsley CW; 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.
Jazyk:	angličtina
Zdroj:	ACS chemical neuroscience [ACS Chem Neurosci] 2017 Apr 19; Vol. 8 (4), pp. 866-883. Date of Electronic Publication: 2017 Jan 10.
DOI:	10.1021/acschemneuro.6b00429
Abstrakt:	Both historical clinical and recent preclinical data suggest that the M 1 muscarinic 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 M 1 activation. Efforts then shifted to focus on selective activation of M 1 via either allosteric agonists or positive allosteric modulators (PAMs). While M 1 PAMs 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 M 1 ago-PAMs. Our data demonstrate that closely related M 1 PAMs 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 M 1 PAM 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 M 1 responses, 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 M 1 PAMs.
Databáze:	MEDLINE
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