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

Content Provider	PubMed Central
Author	Lebon, Guillaume Langmead, Christopher J. Tehan, Ben G. Hulme, Edward C.
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.
Related Links	http://dx.doi.org/10.1124/mol.108.050963
Ending Page	341
Page Count	11
Starting Page	331
File Format	PDF
ISSN	0026895X
e-ISSN	15210111
Journal	Molecular Pharmacology
Issue Number	2
Volume Number	75
Language	English
Publisher	American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2009-02-01
Access Restriction	Open
Rights Holder	American Society for Pharmacology and Experimental Therapeutics
Subject Keyword	Molecular Medicine Pharmacology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Molecular Medicine Pharmacology

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