Allosteric Binding Sites on Muscarinic Acetylcholine Receptors

Abstract

In this issue of Molecular Pharmacology, Trä nkle et al. (p. 1597) present new findings regarding the existence of a second allosteric site on the M 2 muscarinic acetylcholine receptor (M 2 mAChR). The M 2 mAChR is a prototypic class A G proteincoupled receptor (GPCR) that has proven to be a very useful model system to study the molecular mechanisms involved in the binding of allosteric GPCR ligands. Previous studies have identified several allosteric muscarinic ligands, including the acetylcholinesterase inhibitor tacrine and the bis-pyridinium derivative 4,4Ј-bis-[(2,6-dichloro-benzyloxy-imino)-methyl]-1,1Ј-propane-1,3-diyl-bis-pyridinium dibromide (Duo3), which, in contrast to conventional allosteric muscarinic ligands, display concentration-effect curves with slope factors Ͼ1. By analyzing the interactions of tacrine and Duo3 with other allo-

All muscarinic acetylcholine receptors (M1-M5) are expressed in murine brain microvascular endothelium

“…41 We validated this subdivision against the residues known to be involved in ligand-receptor interactions of both cavities in the crystal structures 42 . From our alignment, the orthosteric cavity reflects the full conservation of the residues 29, 43 (Fig. 6A–C).…”

“…M 1 , M 3 , and M 5 are coupled with the G q protein and, via phospholipase C signaling pathway, generate cytosolic calcium transients; M 2 and M 4 , on the other hand, couple with the G i protein inhibiting the adenylyl cyclase 25, 26 . While obtaining mAChRs subtype-selective ligands is a primary goal in drug development 25, 27 , previous attempts have failed due to the highly conserved structure of the orthosteric binding site across the muscarinic receptor family members 28, 29 . On the other hand, the allosteric binding site seems to hold promise as a specific pharmacological target 27 .…”

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…Muscarinic receptors have alternative binding sites called allosteric sites, which provide a strategy in the quest for M1‐selective compounds. Allosteric sites are not fully conserved between receptor subtypes and are topographically distinct from the orthosteric binding site . They therefore represent a target for the discovery of selective agonists and eliminate one of the main causes behind the failure of orthosteric ligands: side effects…”

Synthesis of novel and functionally selective non‐competitive muscarinic antagonists as chemical probes

“…Allosteric ligands exert their effects by modulating the binding affinity and downstream efficacy of the orthosterically bound ligand . The use of allosteric muscarinic ligands, gallamine, and alcuronium, in site‐directed mutagenesis studies provided evidence for the “common” allosteric site . The existence of a second allosteric site was proposed when indolocarbazole (KT5720) was found to allosterically enhance the binding of acetylcholine and N ‐methylscopolamine (NMS) at the M 1 –M 4 receptors .…”

“…[8] The use of allosteric muscarinic ligands, gallamine, and alcuronium, in site-directed mutagenesis studies provided evidence for the "common" allosteric site. [9] The existence of a second allosteric site was proposed when indolocarbazole (KT5720) was found to allosterically enhance the binding of acetylcholine and N-methylscopolamine (NMS) at the M 1 -M 4 receptors. [10] Numerous selective muscarinic ligands have been identified, including positive allosteric modulators (PAMs) and putative bitopic agonists.…”