Allosteric Binding Sites on Muscarinic Acetylcholine Receptors
2005; American Society for Pharmacology and Experimental Therapeutics; Volume: 68; Issue: 6 Linguagem: Inglês
10.1124/mol.105.019141
ISSN1521-0111
Autores Tópico(s)Monoclonal and Polyclonal Antibodies Research
ResumoIn this issue of Molecular Pharmacology , Tränkle 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 protein-coupled 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 4,4′-bis-[(2,6-dichloro-benzyloxy-imino)-methyl]-1,1′-propane-1,3-diyl-bis-pyridinium dibromide (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 `common9 allosteric binding site, Tränkle et al. provide evidence suggesting that two allosteric agents and one orthosteric ligand may be able to bind to the M 2 mAChR simultaneously. Moreover, studies with mutant mAChRs indicated that the M 2 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 subdomain of the receptor9s allosteric binding cleft. Because 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 Tränkle et al. should be of considerable general interest.
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