Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists

Proc Natl Acad Sci U S A. 2018 Nov 20;115(47):12046-12050. doi: 10.1073/pnas.1813988115. Epub 2018 Nov 7.


Drugs that treat chronic obstructive pulmonary disease by antagonizing the M3 muscarinic acetylcholine receptor (M3R) have had a significant effect on health, but can suffer from their lack of selectivity against the M2R subtype, which modulates heart rate. Beginning with the crystal structures of M2R and M3R, we exploited a single amino acid difference in their orthosteric binding pockets using molecular docking and structure-based design. The resulting M3R antagonists had up to 100-fold selectivity over M2R in affinity and over 1,000-fold selectivity in vivo. The crystal structure of the M3R-selective antagonist in complex with M3R corresponded closely to the docking-predicted geometry, providing a template for further optimization.

Keywords: G protein-coupled receptor; crystal structure; drug design; muscarinic receptor; subtype selectivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Molecular Docking Simulation / methods
  • Muscarinic Antagonists / chemistry
  • Muscarinic Antagonists / metabolism
  • Receptor, Muscarinic M2 / antagonists & inhibitors
  • Receptor, Muscarinic M2 / metabolism
  • Receptor, Muscarinic M3 / antagonists & inhibitors*
  • Receptor, Muscarinic M3 / genetics*


  • CHRM3 protein, human
  • Muscarinic Antagonists
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • Acetylcholine

Associated data

  • PDB/5ZHP