Received for publication September 21, 2005.
Revised September 23, 2005.
Accepted for publication September 23, 2005.

Allosteric Binding Sites on Muscarinic Acetylcholine Receptors (Relates to Article by Trankle, et al. FastForward 12 September 2005)

Abstract

In this issue of Molecular Pharmacology, Trankle et al. (p. xx) present new findings regarding the existence of a second allosteric site on the M₂ muscarinic acetylcholine receptor (M₂ mAChR). The M₂ mAChR is a prototypic class A G protein-coupled receptor (GPCR) that has proven 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 Duo3, which, in contrast to conventional allosteric muscarinic ligands, display concentration-effect curves with slope factors >1. By analyzing the interactions of tacrine and Duo3 with other allosteric muscarinic agents predicted to bind to the previously identified 'common' allosteric binding site, Tränkle et al. (p. xx) provide evidence suggesting that two allosteric agents and one orthosteric ligand may be able to bind to the M₂ mAChR simultaneously. Moreover, studies with mutant mAChRs indicated that the M₂ receptor epitopes involved in the binding of tacrine and Duo3 may not be identical. Molecular modeling and ligand docking studies suggested that the additional allosteric site probably represents a sub-domain of the receptor's allosteric binding cleft. Since allosteric binding sites have been found on many other GPCRs and drugs interacting with these sites are thought to have great therapeutic potential, the study by Trankle et al. should be of considerable general interest.

Key words: Muscarinic cholinergic, Structure-activity relationships and modeling

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