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Molecular Pharmacology

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Research ArticleArticle

The M1 Muscarinic Receptor Allosteric Agonists AC-42 and 1-[1′-(2-Methylbenzyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one Bind to a Unique Site Distinct from the Acetylcholine Orthosteric Site

Marlene A. Jacobson, Constantine Kreatsoulas, Danette M. Pascarella, Julie A. O'Brien and Cyrille Sur
Molecular Pharmacology October 2010, 78 (4) 648-657; DOI: https://doi.org/10.1124/mol.110.065771
Marlene A. Jacobson
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Constantine Kreatsoulas
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Danette M. Pascarella
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Julie A. O'Brien
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Cyrille Sur
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Abstract

Activation of M1 muscarinic receptors occurs through orthosteric and allosteric binding sites. To identify critical residues, site-directed mutagenesis and chimeric receptors were evaluated in functional calcium mobilization assays to compare orthosteric agonists, acetylcholine and xanomeline, M1 allosteric agonists AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride), TBPB (1-[1′-(2-methylbenzyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one), and the clozapine metabolite N-desmethylclozapine. A minimal epitope has been defined for AC-42 that comprises the first 45 amino acids, the third extracellular loop, and seventh transmembrane domain (Mol Pharmacol 61:1297–1302, 2002). Using chimeric M1 and M3 receptor constructs, the AC-42 minimal epitope has been extended to also include transmembrane II. Phe77 was identified as a critical residue for maintenance of AC-42 and TBPB agonist activity. In contrast, the functional activity of N-desmethylclozapine did not require Phe77. To further map the binding site of AC-42, TBPB, and N-desmethylclozapine, point mutations previously reported to affect activities of M1 orthosteric agonists and antagonists were studied. Docking into an M1 receptor homology model revealed that AC-42 and TBPB share a similar binding pocket adjacent to the orthosteric binding site at the opposite face of Trp101. In contrast, the activity of N-desmethylclozapine was generally unaffected by the point mutations studied, and the docking indicated that N-desmethylclozapine bound to a site distinct from AC-42 and TBPB overlapping with the orthosteric site. These results suggest that structurally diverse allosteric agonists AC-42, TBPB, and N-desmethylclozapine may interact with different subsets of residues, supporting the hypothesis that M1 receptor activation can occur through at least three different binding domains.

Footnotes

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.065771.

  • ABBREVIATIONS:

    TM
    transmembrane
    AC-42
    4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride
    TBPB
    1-[1′-(2-methylbenzyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one
    QNB
    quinuclidinyl benzilate
    NMS
    N-methylscopolamine
    CHONFAT
    Chinese hamster ovary nuclear factor of activated T-cells
    FLIPR
    fluorescence imaging plate reader.

  • Received April 22, 2010.
  • Accepted July 21, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
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Research ArticleArticle

The M1 Muscarinic Receptor Allosteric Agonists AC-42 and 1-[1′-(2-Methylbenzyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one Bind to a Unique Site Distinct from the Acetylcholine Orthosteric Site

Marlene A. Jacobson, Constantine Kreatsoulas, Danette M. Pascarella, Julie A. O'Brien and Cyrille Sur
Molecular Pharmacology October 1, 2010, 78 (4) 648-657; DOI: https://doi.org/10.1124/mol.110.065771

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Research ArticleArticle

The M1 Muscarinic Receptor Allosteric Agonists AC-42 and 1-[1′-(2-Methylbenzyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one Bind to a Unique Site Distinct from the Acetylcholine Orthosteric Site

Marlene A. Jacobson, Constantine Kreatsoulas, Danette M. Pascarella, Julie A. O'Brien and Cyrille Sur
Molecular Pharmacology October 1, 2010, 78 (4) 648-657; DOI: https://doi.org/10.1124/mol.110.065771
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