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Molecular Pharmacology

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Research ArticleArticle

Mutagenic Mapping Suggests a Novel Binding Mode for Selective Agonists of M1 Muscarinic Acetylcholine Receptors

Guillaume Lebon, Christopher J. Langmead, Ben G. Tehan and Edward C. Hulme
Molecular Pharmacology February 2009, 75 (2) 331-341; DOI: https://doi.org/10.1124/mol.108.050963
Guillaume Lebon
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Christopher J. Langmead
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Ben G. Tehan
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Edward C. Hulme
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Abstract

Point mutations and molecular modeling have been used to study the activation of the M1 muscarinic acetylcholine receptor (mAChR) by the functionally selective agonists 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine (AC-42), and 1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone (77-LH-28-1), comparing them with N-desmethylclozapine (NDMC) and acetylcholine (ACh). Unlike NDMC and ACh, the activities of AC-42 and 77-LH-28-1 were undiminished by mutations of Tyr404 and Cys407 (transmembrane helix 7), although they were reduced by mutations of Tyr408. Signaling by AC-42, 77-LH-28-1, and NDMC was reduced by L102A and abolished by D105E, suggesting that all three may interact with transmembrane helix 3 at or near the binding site Asp105 to activate the M1 mAChR. In striking contrast to NDMC and ACh, the affinities of AC-42 and 77-LH-28-1 were increased 100-fold by W101A, and their signaling activities were abolished by Y82A. Tyr82 and Leu102 contact the indole ring of Trp101 in a structural model of the M1 mAChR. We suggest the hypothesis that the side chain of Trp101 undergoes conformational isomerization, opening a novel binding site for the aromatic side chain of the AC-42 analogs. This may allow the positively charged piperidine nitrogen of the ligands to access the neighboring Asp105 carboxylate to activate signaling following a vector within the binding site that is distinct from that of acetylcholine. NDMC does not seem to use this mechanism. Subtype-specific differences in the free energy of rotation of the side chain and indole ring of Trp101 might underlie the M1 selectivity of the AC-42 analogs. Tryptophan conformational isomerization may open up new avenues in selective muscarinic receptor drug design.

Footnotes

  • This work was supported by GlaxoSmithKline and by the Medical Research Council (United Kingdom) [Grant in Aid U.1175.03.003.00008.01].

  • ABBREVIATIONS: mAChR, muscarinic acetylcholine receptor; NSA, novel selective agonist; ACh, acetylcholine; TM, transmembrane domain; NMS, (-)-N-methyl scopolamine; PhI, phosphoinositide; NDMC, N-desmethylclozapine; AC-42, 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine; 77-LH-28-1, 1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone; PBS, phosphate-buffered saline; DMSO, dimethyl sulfoxide.

  • ↵1 Current affiliation: Division of Structural Studies, Laboratory of Molecular Biology, Cambridge, United Kingdom.

    • Received July 31, 2008.
    • Accepted November 11, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (2)
Molecular Pharmacology
Vol. 75, Issue 2
1 Feb 2009
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Research ArticleArticle

Mutagenic Mapping Suggests a Novel Binding Mode for Selective Agonists of M1 Muscarinic Acetylcholine Receptors

Guillaume Lebon, Christopher J. Langmead, Ben G. Tehan and Edward C. Hulme
Molecular Pharmacology February 1, 2009, 75 (2) 331-341; DOI: https://doi.org/10.1124/mol.108.050963

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Research ArticleArticle

Mutagenic Mapping Suggests a Novel Binding Mode for Selective Agonists of M1 Muscarinic Acetylcholine Receptors

Guillaume Lebon, Christopher J. Langmead, Ben G. Tehan and Edward C. Hulme
Molecular Pharmacology February 1, 2009, 75 (2) 331-341; DOI: https://doi.org/10.1124/mol.108.050963
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