Dualsteric GPCR targeting and functional selectivity: the paradigmatic M(2) muscarinic acetylcholine receptor

Drug Discov Today Technol. 2013 Summer;10(2):e245-52. doi: 10.1016/j.ddtec.2012.12.003.

Abstract

Muscarinic acetylcholine receptors belong to Class Aseven transmembrane helical receptors and serve as important drug targets in the treatment of various diseases such as chronic obstructive pulmonary disease, overactive bladder, bronchial asthma and glaucoma. Despite intensive research the discovery of experimental ligands which activate or block specific muscarinic receptor subtypes has only been successful for the M1 and M4 subtypes but remains a challenging task at the other subtypes. In recent years, ligands have been introduced which bind simultaneously to the acetylcholine binding site, that is, the orthosteric site, and to an allosteric binding site. These so-called dualsteric ligands display M2 subtype preference due to the addressing of the allosteric binding site. As proven recently, dualsteric receptor activation goes along with a pronounced signaling bias which follows clear structure–bias-relationships. Dualsteric receptor targeting might represent a common strategy to generate functional selectivity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Binding Sites
  • Ligands
  • Protein Binding
  • Receptor, Muscarinic M2 / chemistry
  • Receptor, Muscarinic M2 / metabolism*

Substances

  • Ligands
  • Receptor, Muscarinic M2