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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor.

Xanomeline is a functionally selective M1/M4 muscarinic acetylcholine receptor agonist. We have previously identified a novel mode of interaction of this ligand with the muscarinic M1 receptor that involves persistent binding and activation of the receptor after extensive washout. In the present study, we tested the hypothesis that xanomeline also binds in a wash-resistant manner to muscarinic receptor subtypes where it exhibits low or no efficacy, such as the M5 receptor subtype. A secondary hypothesis is that persistent binding of xanomeline to the M5 receptor results in wash-resistant antagonism to the effects of full agonists. These hypotheses were tested in Chinese hamster ovary cells stably expressing the M5 receptor. In these cells, xanomeline is a weak partial agonist and is able to inhibit carbachol-induced phosphoinositide hydrolysis to the maximal response of xanomeline in a concentration-dependent manner. Pretreatment with xanomeline followed by extensive washing resulted in a significant wash-resistant reduction in receptor affinity with no significant change in maximal cell surface receptor density. This was associated with wash-resistant antagonism of carbachol-induced activation of phosphoinositide hydrolysis at the M5 receptor, reflected as decreased carbachol potency without a change in the maximal response. Similar experiments using the partial agonist pilocarpine demonstrated a reduction of pilocarpine potency as well as maximal response. Our results clearly indicate that wash-resistant binding of xanomeline to the muscarinic M5 receptor is accompanied by persistent antagonism of receptor function. They also suggest a relationship between the efficacy of xanomeline and the functional consequences of its wash-resistant binding at different muscarinic receptor subtypes.[1]


  1. Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor. Grant, M.K., El-Fakahany, E.E. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
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