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Molecular Pharmacology

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Research ArticleArticle

Discovery and Characterization of Novel Allosteric Potentiators of M1 Muscarinic Receptors Reveals Multiple Modes of Activity

Joy E. Marlo, Colleen M. Niswender, Emily L. Days, Thomas M. Bridges, Yun Xiang, Alice L. Rodriguez, Jana K. Shirey, Ashley E. Brady, Tasha Nalywajko, Qingwei Luo, Cheryl A. Austin, Michael Baxter Williams, Kwangho Kim, Richard Williams, Darren Orton, H. Alex Brown, Craig W. Lindsley, C. David Weaver and P. Jeffrey Conn
Molecular Pharmacology March 2009, 75 (3) 577-588; DOI: https://doi.org/10.1124/mol.108.052886
Joy E. Marlo
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Colleen M. Niswender
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Emily L. Days
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Thomas M. Bridges
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Yun Xiang
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Alice L. Rodriguez
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Jana K. Shirey
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Ashley E. Brady
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Tasha Nalywajko
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Qingwei Luo
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Cheryl A. Austin
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Michael Baxter Williams
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Kwangho Kim
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Richard Williams
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Darren Orton
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H. Alex Brown
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Craig W. Lindsley
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C. David Weaver
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P. Jeffrey Conn
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Abstract

Activators of M1 muscarinic acetylcholine receptors (mAChRs) may provide novel treatments for schizophrenia and Alzheimer's disease. Unfortunately, the development of M1-active compounds has resulted in nonselective activation of the highly related M2 to M5 mAChR subtypes, which results in dose-limiting side effects. Using a functional screening approach, we identified several novel ligands that potentiated agonist activation of M1 with low micromolar potencies and induced 5-fold or greater leftward shifts of the acetylcholine (ACh) concentration-response curve. These ligands did not compete for binding at the ACh binding site, indicating that they modulate receptor activity by binding to allosteric sites. The two most selective compounds, cyclopentyl 1,6-dimethyl-4-(6-nitrobenzo[d][1,3]-dioxol-5-yl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (VU0090157) and (E)-2-(4-ethoxyphenylamino)-N′-((2-hydroxynaphthalen-1-yl)methylene)acetohydrazide (VU0029767), induced progressive shifts in ACh affinity at M1 that were consistent with their effects in a functional assay, suggesting that the mechanism for enhancement of M1 activity by these compounds is by increasing agonist affinity. These compounds were strikingly different, however, in their ability to potentiate responses at a mutant M1 receptor with decreased affinity for ACh and in their ability to affect responses of the allosteric M1 agonist, 1-[1′-(2-tolyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one. Furthermore, these two compounds were distinct in their abilities to potentiate M1-mediated activation of phosphoinositide hydrolysis and phospholipase D. The discovery of multiple structurally distinct positive allosteric modulators of M1 is an exciting advance in establishing the potential of allosteric modulators for selective activation of this receptor. These data also suggest that structurally diverse M1 potentiators may act by distinct mechanisms and differentially regulate receptor coupling to downstream signaling pathways.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Mental Health [Grants MH073676, MH082867]; The Alzheimer's Association [Grant IIRG-07-57131]; the Vanderbilt Institute of Chemical Biology [Integrative Training in Therapeutic Discovery Grant T90-DA22873]; and LIPID Metabolites And Pathways Strategy [Grant U54-GM69339].

  • J.E.M. and C.M.N. contributed equally to this work.

  • ABBREVIATIONS: AD, Alzheimer's disease; GPCR, G protein-coupled receptor; mGluR, metabotropic glutamate receptor; CHO, Chinese hamster ovary; DMSO, dimethyl sulfoxide; ACh, acetylcholine; TBPB, 1-[1′-(2-tolyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; PAM, positive allosteric modulator; PtdMeOH, 1,2-dipalmitoyl-sn-glycero-3-phosphomethanol, phosphatidylmethanol; VU0090157, cyclopentyl 1,6-dimethyl-4-(6-nitrobenzo[d][1,3]dioxol-5-yl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; VU0029767, (E)-2-(4-ethoxyphenylamino)-N′-((2-hydroxynaphthalen-1-yl)methylene)acetohydrazide; VU0119498, 1-(4-bromobenzyl)indoline-2,3-dione; mAChR, muscarinic acetylcholine receptor; FBS, fetal bovine serum; DMEM, Dulbecco's modified Eagle's medium; FDSS, Functional Drug Screening System; PI, phosphatidylinositol; LC-MS, liquid chromatography-mass spectrometry; WT, wild type; PLD, phospholipase D; [3H]NMS, l-[N-methyl-3H]scopolamine.

    • Received October 17, 2008.
    • Accepted December 1, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (3)
Molecular Pharmacology
Vol. 75, Issue 3
1 Mar 2009
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Research ArticleArticle

Discovery and Characterization of Novel Allosteric Potentiators of M1 Muscarinic Receptors Reveals Multiple Modes of Activity

Joy E. Marlo, Colleen M. Niswender, Emily L. Days, Thomas M. Bridges, Yun Xiang, Alice L. Rodriguez, Jana K. Shirey, Ashley E. Brady, Tasha Nalywajko, Qingwei Luo, Cheryl A. Austin, Michael Baxter Williams, Kwangho Kim, Richard Williams, Darren Orton, H. Alex Brown, Craig W. Lindsley, C. David Weaver and P. Jeffrey Conn
Molecular Pharmacology March 1, 2009, 75 (3) 577-588; DOI: https://doi.org/10.1124/mol.108.052886

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Research ArticleArticle

Discovery and Characterization of Novel Allosteric Potentiators of M1 Muscarinic Receptors Reveals Multiple Modes of Activity

Joy E. Marlo, Colleen M. Niswender, Emily L. Days, Thomas M. Bridges, Yun Xiang, Alice L. Rodriguez, Jana K. Shirey, Ashley E. Brady, Tasha Nalywajko, Qingwei Luo, Cheryl A. Austin, Michael Baxter Williams, Kwangho Kim, Richard Williams, Darren Orton, H. Alex Brown, Craig W. Lindsley, C. David Weaver and P. Jeffrey Conn
Molecular Pharmacology March 1, 2009, 75 (3) 577-588; DOI: https://doi.org/10.1124/mol.108.052886
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