Allosteric modulators targeting CNS muscarinic receptors.

Allosteric modulators targeting CNS muscarinic receptors. Neuropharmacology. 2017 Sep 18;: Authors: Bock A, Schrage R, Mohr K Abstract 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 ...
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research