Inhibition of the actions of carbachol and DFP on guinea pig isolated atria by alkane-bis-ammonium compounds

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

“…The M 2 mAChR is the first GPCR for which synthetic allosteric modulators were identified (Lüllman et al, 1969;Clark and Mitchelson, 1976). Structural studies have established a key role for positively charged modulators to interact with a well defined allosteric site in the extracellular vestibule of these receptors (Dror et al, 2013).…”

Interactions of Orthosteric and Allosteric Ligands with [3H]Dimethyl-W84 at the Common Allosteric Site of Muscarinic M2 Receptors

“…This phenomenon has been intensively studied on muscarinic acetylcholine receptors (Tuček and Proška, 1995;Birdsall et al, 1996;Ellis, 1997;Holzgrabe and Mohr, 1998). Many features of allosteric modulation have been demonstrated: enhancement of agonist binding (Birdsall et al, 1997;Jakubík et al, 1997;Lazareno et al, 1998; and action , absolute subtype selectivity of allosteric action (Birdsall et al, 1997;Lazareno et al, 1998Lazareno et al, , 1999, mapping of ligand receptor interactions Trä nkle et al, 1998a), defined maximum effects on function (Lü llmann et al, 1969;Clark and Mitchelson, 1976), and modulation of receptor signaling efficacy (Zahn et al, 2002). All five muscarinic receptor subtypes are sensitive to allosteric modulation (Ellis et al, 1991) with many of the typical quaternary ammonium modulators such as gallamine, alcuronium, W84, and dimethyl-W84, exhibiting an M 2 subtype selectivity.…”

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

“…However, the phenomenon had actually been demonstrated (though largely unappreciated) many decades earlier. For instance, Lüllmann et al (1969) were the first to propose a putative allosteric mechanism of action for a novel series of synthetic antimuscarinic agents based on tissue bioassay studies. A seminal report by Clark and Mitchelson (1976) described and quantified the mechanism of action of gallamine as a negative allosteric modulator of the M 2 muscarinic acetylcholine receptor (mAChR) in an isolated atria bioassay, and this was confirmed in radioligand binding studies by Stockton et al (1983).…”