PMID- 28001356 OWN - NLM STAT- MEDLINE DCOM- 20170502 LR - 20181113 IS - 1948-7193 (Electronic) IS - 1948-7193 (Linking) VI - 8 IP - 4 DP - 2017 Apr 19 TI - Diverse Effects on M(1) Signaling and Adverse Effect Liability within a Series of M(1) Ago-PAMs. PG - 866-883 LID - 10.1021/acschemneuro.6b00429 [doi] AB - 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. FAU - Rook, Jerri M AU - Rook JM AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Abe, Masahito AU - Abe M AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Cho, Hyekyung P AU - Cho HP AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Nance, Kellie D AU - Nance KD AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Luscombe, Vincent B AU - Luscombe VB AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Adams, Jeffrey J AU - Adams JJ AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Dickerson, Jonathan W AU - Dickerson JW AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Remke, Daniel H AU - Remke DH AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Garcia-Barrantes, Pedro M AU - Garcia-Barrantes PM AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Engers, Darren W AU - Engers DW AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Engers, Julie L AU - Engers JL AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Chang, Sichen AU - Chang S AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Foster, Jarrett J AU - Foster JJ AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Blobaum, Anna L AU - Blobaum AL AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Niswender, Colleen M AU - Niswender CM AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Jones, Carrie K AU - Jones CK AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Conn, P Jeffrey AU - Conn PJ AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. FAU - Lindsley, Craig W AU - Lindsley CW AUID- ORCID: 0000-0003-0168-1445 AD - Department of Pharmacology, double daggerDepartment of Chemistry, section signVanderbilt Center for Neuroscience Drug Discovery, parallelVanderbilt Kennedy Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-6600, United States. LA - eng GR - R01 AG051626/AG/NIA NIH HHS/United States GR - R01 MH082867/MH/NIMH NIH HHS/United States GR - U19 MH106839/MH/NIMH NIH HHS/United States GR - U54 HD083211/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20170110 PL - United States TA - ACS Chem Neurosci JT - ACS chemical neuroscience JID - 101525337 RN - 0 (Muscarinic Agonists) RN - 0 (Receptor, Muscarinic M1) SB - IM MH - Allosteric Regulation/*drug effects MH - Animals MH - *Drug Discovery MH - Humans MH - Mice MH - Muscarinic Agonists/chemical synthesis/*chemistry/*pharmacology MH - Rats MH - Receptor, Muscarinic M1/*drug effects/metabolism MH - Structure-Activity Relationship PMC - PMC5460155 MID - NIHMS858301 OTO - NOTNLM OT - M1 OT - ago-PAM OT - agonist OT - muscarinic acetylcholine receptor OT - positive allosteric modulator (PAM) OT - seizure COIS- Notes The authors are developing M(1) PAMs for the treatment of schizophrenia and AD, and have an open-IND for the same as well as a patent portfolio of M(1) PAMs. The authors declare no competing financial interest. EDAT- 2016/12/22 06:00 MHDA- 2017/05/04 06:00 PMCR- 2018/04/19 CRDT- 2016/12/22 06:00 PHST- 2016/12/22 06:00 [pubmed] PHST- 2017/05/04 06:00 [medline] PHST- 2016/12/22 06:00 [entrez] PHST- 2018/04/19 00:00 [pmc-release] AID - 10.1021/acschemneuro.6b00429 [doi] PST - ppublish SO - ACS Chem Neurosci. 2017 Apr 19;8(4):866-883. doi: 10.1021/acschemneuro.6b00429. Epub 2017 Jan 10.