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Review
. 2010 Aug 30;3(9):2838-2860.
doi: 10.3390/ph3092838.

Allosteric Modulation of Muscarinic Acetylcholine Receptors

Jan Jakubík  1 , Esam E El-Fakahany  2
Affiliations
Review

Allosteric Modulation of Muscarinic Acetylcholine Receptors

Jan Jakubík et al. Pharmaceuticals (Basel). .

Abstract

An allosteric modulator is a ligand that binds to an allosteric site on the receptor and changes receptor conformation to produce increase (positive cooperativity) or decrease (negative cooperativity) in the binding or action of an orthosteric agonist (e.g., acetylcholine). Since the identification of gallamine as the first allosteric modulator of muscarinic receptors in 1976, this unique mode of receptor modulation has been intensively studied by many groups. This review summarizes over 30 years of research on the molecular mechanisms of allosteric interactions of drugs with the receptor and for new allosteric modulators of muscarinic receptors with potential therapeutic use. Identification of positive modulators of acetylcholine binding and function that enhance neurotransmission and the discovery of highly selective allosteric modulators are mile-stones on the way to novel therapeutic agents for the treatment of schizophrenia, Alzheimer's disease and other disorders involving impaired cognitive function.

Keywords: Alzheimer’s disease; allosteric modulation; muscarinic acetylcholine receptors; schizophrenia.

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Figures

Figure 1
Figure 1
Structures of prototypical allosteric modulators of muscarinic receptors.
Figure 2
Figure 2
Structures of toxiferous, strychnos and vinca alkaloids.
Figure 3
Figure 3
Structures of symmetric allosteric modulators of muscarinic receptors.
Figure 4
Figure 4
Location of orthosteric and allosteric binding sites on a homology model of M2 muscarinic receptor. Orientation, Extracellular, top; (a) TM5, front; (b) TM7, front. Structure, α-helices, red; 3.10 helices, purple; coil, white; turn, cyan; disulfide bridge, yellow; orthosteric site, blue; allosteric site, green. Ligands, orthosteric site, NMS; allosteric site, strychnine.
Figure 5
Figure 5
Structures of “atypical” allosteric modulators of muscarinic receptors.
Figure 6
Figure 6
Structures of radiolabeled allosteric modulators of muscarinic receptors.
Figure 7
Figure 7
Structure of thiochrome.
Figure 8
Figure 8
Structure of M1 selective allosteric modulators.
Figure 9
Figure 9
Structure of M4-selective allosteric modulators.
Figure 10
Figure 10
Structures of muscarinic ectopic agonists.
See this image and copyright information in PMC

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References

    1. Dale H.H. The action of certain esters and ethers of choline and their relation to muscarine. J. Pharmacol. 1914;6:147–190.
    1. Loewi O. Über humorale Übertragbarkeit der Herznervenwirkung. I. Pflügers Archiv. 1921;189:239–242. doi: 10.1007/BF01738910. - DOI
    1. Bonner T.I., Buckley N.J., Young A.C., Brann M.R. Identification of a family of muscarinic acetylcholine receptor genes. Science. 1987;237:527–532. - PubMed
    1. Caulfield M.P. Muscarinic receptors--characterization, coupling and function. Pharmacol. Ther. 1993;58:319–379. - PubMed
    1. Levey A.I. Immunological localization of m1-m5 muscarinic acetylcholine receptors in peripheral tissues and brain. Life Sci. 1993;52:441–448. - PubMed

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