Allosteric modulators targeting CNS muscarinic receptors


  • A. Bock
  • R. Schrage
  • K. Mohr


  • Neuropharmacology


  • Neuropharmacology 136 (Part C): 427-437


  • Muscarinic acetylcholine receptors are G protein-coupled receptors (GPCRs) which are broadly expressed in the central nervous system (CNS) and other tissues in the periphery. They emerge as important drug targets for a number of diseases including Alzheimer's disease, Parkinson's disease, and schizophrenia. Muscarinic receptors are divided into five subtypes (M1-M5) of which M1-M4 have been crystalized. All subtypes possess at least one allosteric binding site which is located in the extracellular region of the receptor on top of the ACh (i.e. orthosteric) binding site. The former can be specifically targeted by chemical compounds (mostly small molecules) and binding of such allosteric modulators affects the affinity and/or efficacy of orthosteric ligands. This allows highly specific modulation of GPCR function and, from a drug discovery point of view, may be advantageous in terms of subtype selectivity and biased signaling. There is a plethora of allosteric modulators for all five muscarinic receptor subtypes. This review presents the basic principles of allosteric modulation of GPCRs on both the molecular and structural level focusing on allosteric modulators of the muscarinic receptor family. Further we discuss dualsteric (i.e. bitopic orthosteric/allosteric) ligands emphasizing their potential in modulating muscarinic receptor dynamics and signaling. The common mechanisms of muscarinic receptor allosteric modulation have been proven to be generalizable and are at play at many, if not all GPCRs. Given this paradigmatic role of muscarinic receptors we suggest that also new developments in muscarinic allosteric modulation may also be extended to other members of the GPCR superfamily.