Chapter 12 Allosteric regulation of muscarinic receptors

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This chapter describes some of the work on the location of the allosteric site on muscarinic receptors and presents recent data on the binding of strychnine to this site. Much of the work on allosteric interactions at muscarinic receptors, including the initial studies, has utilized the neuromuscular blocker gallamine. This is a highly charged ligand, bearing three positive charges, and exhibits negatively cooperative interactions with a range of muscarinic agonists and antagonists. Paradoxically, gallamine dramatically slows down the association and dissociation kinetics of quaternized muscarinic antagonists, such as N-methyl scopolamine (NMS), when it binds to muscarinic receptors—in most instances decreases in affinity are associated with faster, and not slower, kinetics. The chapter concludes that strychnine, in addition to its actions on glycine receptors, acts as an allosteric ligand at ml-m4 muscarinic receptors and is able to quantitate its binding properties. Even smaller effect of strychnine on the binding properties of NMS and acetylcholine (ACh) at ml receptors is illustrated in the chapter.

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    The clinical use of allosteric compounds has recently attracted more attention (57–59). These modulators can be used at saturating concentrations, because their effects are only revealed in the presence of endogenous ligands (e.g. neutral allosteric ligands), potentially reducing adverse effects (60–62). The design of allosteric ligands with biased signaling properties, as in the case of PDC113.824, offers not only the advantage of specificity for a single GPCR, but also selectivity for a specific subset of signaling pathways, further reducing unwanted side effects.

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