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Review
. 2009 Mar;30(3):148-55.
doi: 10.1016/j.tips.2008.12.002. Epub 2009 Feb 7.

Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders

P Jeffrey Conn  1 , Carrie K Jones, Craig W Lindsley
Affiliations
Review

Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders

P Jeffrey Conn et al. Trends Pharmacol Sci. 2009 Mar.

Abstract

Muscarinic acetylcholine receptors (mAChRs) have long been viewed as viable targets for novel therapeutic agents for the treatment of Alzheimer's disease (AD) and other disorders involving impaired cognitive function. More recent evidence indicates that mAChR activators might also have utility in treating psychosis and other symptoms associated with schizophrenia and other central nervous system (CNS) disorders. Efforts to develop mAChR subtype-selective agonists have been hampered by difficulty in achieving high selectivity for individual mAChR subtypes important for CNS function (M(1) and M(4)) and adverse effects due to activation of peripheral mAChRs (especially M(2) and M(3)). Major advances have now been achieved in the discovery of allosteric agonists and positive allosteric modulators of M(1) and M(4) that show greater selectivity for individual mAChR subtypes than do previous mAChR agonists. Early studies indicate that these allosteric mAChR activators have properties needed for optimization as potential clinical candidates and have robust effects in animal models that predict efficacy in the treatment of AD, schizophrenia and related disorders.

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Conflict of interest statement

Conflict-of-interest statement

P.J.C. has received compensation over the past two years as a consultant from: Merck and Co., Johnson and Johnson, Hoffman La Roche, GlaxoSmithKline, Lundbeck Research USA, Epix Pharmaceuticals, Invitrogen Life Technologies, Evotec Inc., Addex Pharmaceuticals, Michael J. Fox Foundation, Seaside Therapeutics, Cephalon Inc., AstraZeneca USA, NeurOp Inc., Forest Research Institute, LEK Consulting, The Frankel Group, Prestwick Chemical Co., Millipore Corp., Genentech, IMS Health, Primary Insight and Otsuka. P.J.C. has received honoraria as a speaker from: University of Toronto, American Society for Bone and Mineral Research, University of Alabama Birmingham, University of Michigan, Southern Research Inst., Harvard Medical School and the University of North Carolina. P.J.C. receives research support that includes salary support from the National Institutes of Health, Michael J. Fox Foundation, Seaside Therapeutics and Vanderbilt University.

Figures

Figure 1
Figure 1
Schematic illustration of structure and effector systems of the mAChR subtypes. M1, M3 and M5 typically couple to Gaq and associated effector systems such as PLC. M2 and M4 typically couple to Gai/o and associated effectorsystems such as inhibition of adenylyl cyclase (AC) and ion channels, although each receptor subtype can also couple to other signaling pathways. The orthosteric binding site for ACh has been well characterized and resides in the seven transmembrane domain of the receptor. Allosteric ligands bind to other sites on the receptor to either activate (allosteric agonists) or modulate (positive and negative allosteric-site ligands) receptor function. Abbreviations: IP3, inositol (1,4,5)-trisphosphate; ? denotes that exact allosteric binding sites have not been defined.
Figure 2
Figure 2
Early PAMs and allosteric agonists of the mAChRs.
Figure 3
Figure 3
M1 allosteric agonists.
Figure 4
Figure 4
M1 positive allosteric modulators.
Figure 5
Figure 5
M4 positive allosteric modulators.
See this image and copyright information in PMC

References

    1. Brown TA, Zador AM. Hippocampus. In: Shepherd GM, editor. The Synaptic Organization of the Brain. Oxford University Press; 1990. pp. 346–388.
    1. Cooper J, et al. The Biochemical Basis of Neuropharmacology. Oxford University Press; 1996.
    1. Hasselmo ME. The role of acetylcholine in learning and memory. Curr. Opin. Neurobiol. 2006;16:710–715. - PMC - PubMed
    1. Pisani A, et al. Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci. 2007;30:545–553. - PubMed
    1. Fisher A. M1 muscarinic agonists target major hallmarks of Alzheimer’s disease - the pivotal role of brain M1 receptors. Neurodegener. Dis. 2008;5:237–240. - PubMed

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