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Allosteric Modulation of Muscarinic Acetylcholine Receptors

By Karen J Gregory, Patrick M Sexton and Arthur Christopoulos

Abstract

Muscarinic acetylcholine receptors (mAChRs) are prototypical Family A G protein coupled-receptors. The five mAChR subtypes are widespread throughout the periphery and the central nervous system and, accordingly, are widely involved in a variety of both physiological and pathophysiological processes. There currently remains an unmet need for better therapeutic agents that can selectively target a given mAChR subtype to the relative exclusion of others. The main reason for the lack of such selective mAChR ligands is the high sequence homology within the acetylcholine-binding site (orthosteric site) across all mAChRs. However, the mAChRs possess at least one, and likely two, extracellular allosteric binding sites that can recognize small molecule allosteric modulators to regulate the binding and function of orthosteric ligands. Extensive studies of prototypical mAChR modulators, such as gallamine and alcuronium, have provided strong pharmacological evidence, and associated structure-activity relationships (SAR), for a “common” allosteric site on all five mAChRs. These studies are also supported by mutagenesis experiments implicating the second extracellular loop and the interface between the third extracellular loop and the top of transmembrane domain 7 as contributing to the common allosteric site. Other studies are also delineating the pharmacology of a second allosteric site, recognized by compounds such as staurosporine. In addition, allosteric agonists, such as McN-A-343, AC-42 and N-desmethylclozapine, have also been identified. Current challenges to the field include the ability to effectively detect and validate allosteric mechanisms, and to quantify allosteric effects on binding affinity and signaling efficacy to inform allosteric modulator SAR

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Publisher: Bentham Science Publishers Ltd.
OAI identifier: oai:pubmedcentral.nih.gov:2656816
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    Citations

    1. (2002). A model of the human M2 muscarinic acetylcholine receptor.
    2. (1996). Activation of muscarinic acetylcholine receptors via their allosteric binding sites.
    3. (1992). Activation of solubilized G-proteins by muscarinic acetylcholine receptors.
    4. (2006). Ago-allosteric modulation and other types of allostery in dimeric 7TM receptors.
    5. (2002). Allosteric binding sites on cell-surface receptors: novel targets for drug discovery.
    6. (1998). Allosteric interactions at muscarinic cholinoceptors.
    7. (1991). Allosteric interactions at the m1, m2 and m3 muscarinic receptor subtypes.
    8. (2000). Allosteric interactions of staurosporine and other indolocarbazoles with N-[methyl-(3)H]scopolamine and acetylcholine at muscarinic receptor subtypes: identification of a second allosteric site.
    9. (2006). Allosteric interactions with muscarinic acetylcholine receptors: complex role of the conserved tryptophan M2422Trp in a critical cluster of amino acids for baseline affinity, subtype selectivity, and cooperativity.
    10. (2007). Allosteric modulation of g protein-coupled receptors.
    11. (2002). Allosteric modulation of muscarinic receptor signaling: alcuronium-induced conversion of pilocarpine from an agonist into an antagonist.
    12. (1991). Allosteric regulation of cloned m1-m5 muscarinic receptor subtypes.
    13. (2002). Allosteric site on muscarinic acetylcholine receptors: a single amino acid in transmembrane region 7 is critical to the subtype selectivities of caracurine V derivatives and alkane-bisammonium ligands.
    14. (2005). Allosterism at muscarinic receptors: ligands and mechanisms.
    15. (1961). An unusual type of sympathetic ganglionic stimulant.
    16. (2002). Analogs of WIN 62,577 define a second allosteric site on muscarinic receptors.
    17. (2004). Application of a kinetic model to the apparently complex behavior of negative and positive allosteric modulators of muscarinic acetylcholine receptors.
    18. (2005). Asparagine, valine, and threonine in the third extracellular loop of muscarinic receptor have essential roles in the positive cooperativity of strychnine-like allosteric modulators.
    19. (1994). Assessment of the allosteric interactions of the bisquaternary heptane-1,7-bis(dimethyl-3'-phthalimidopropyl)ammonium bromide at M1 and M2 muscarine receptors.
    20. (2005). Atypical muscarinic allosteric modulation: cooperativity between modulators and their atypical binding topology in muscarinic M2 and M2/M5 chimeric receptors.
    21. (2006). Beneficial metabolic effects of M3 muscarinic acetylcholine receptor deficiency.
    22. (1993). Binding of the muscarine receptor antagonist heptane-1,7-bis(dimethyl-3'-phthalimidopropyl)ammonium bromide at cholinoceptor sites.
    23. (2003). Cellular signaling mechanisms for muscarinic acetylcholine receptors.
    24. (2001). Changes of cooperativity between Nmethylscopolamine and allosteric modulators alcuronium and gallamine induced by mutations of external loops of muscarinic M(3) receptors.
    25. (1999). Characterization of the subtype selectivity of the allosteric modulator heptane-1,7-bis-(dimethyl-3'-phthalimidopropyl) ammonium bromide (C7/3-phth) at cloned muscarinic acetylcholine receptors.
    26. (2001). Cholinergic dilation of cerebral blood vessels is abolished in M(5) muscarinic acetylcholine receptor knockout mice.
    27. (2000). Cholinesterase inhibitors: A new class of psychotropic compounds.
    28. (1995). Competition between positive and negative allosteric effectors on muscarinic receptors.
    29. (1999). Competitive and allosteric interactions of 6-chloro-5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H-di benzo[b,e][1, 4]diazepine-11-one hydrochloride (UH-AH 37) at muscarinic receptors, via distinct epitopes.
    30. (2003). Cooperative interactions at M2 muscarinic acetylcholine receptors: structure/activity relationships in stepwise shortened bispyridinium- and bis(ammonio)alkane-type allosteric modulators.
    31. (2006). Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors.
    32. (1995). Detection, quantitation, and verification of allosteric interactions of agents with labeled and unlabeled ligands at G protein-coupled receptors: interactions of strychnine and acetylcholine at muscarinic receptors.
    33. (1993). Development of antisera selective for m4 and m5 muscarinic cholinergic receptors: distribution of m4 and m5 receptors in rat brain.
    34. (1995). Differential alterations in muscarinic receptor subtypes in Alzheimer's disease: implications for cholinergic-based therapies.
    35. dimethyl-W84 at the common allosteric site of muscarinic M2 receptors.
    36. (2002). Discovery of an ectopic activation site on the M(1) muscarinic receptor.
    37. (1997). Divergent modes of action among cationic allosteric modulators of muscarinic M2 receptors.
    38. (1998). Effects of an agonist, allosteric modulator, and antagonist on guanosine-gamma-[35S]thiotriphosphate binding to liposomes with varying muscarinic receptor/Go protein stoichiometry.
    39. (1988). Effects of d-tubocurarine on rat cardiac muscarinic receptors: a comparison with gallamine.
    40. (1988). Effects of tetrahydroaminoacridine on M1 and M2 muscarine receptors.
    41. (1988). Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods.
    42. (2002). Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice.
    43. (1996). Evidence for a multiple binding mode of bispyridinium-type allosteric modulators of muscarinic receptors.
    44. (1995). Expression of m1-m4 muscarinic acetylcholine receptor proteins in rat hippocampus and regulation by cholinergic innervation.
    45. (1990). Expression of muscarinic acetylcholine and dopamine receptor mRNAs in rat basal ganglia.
    46. (2007). Functional selectivity and classical concepts of quantitative pharmacology.
    47. (1983). Heterogeneity of binding sites on cardiac muscarinic receptors induced by the neuromuscular blocking agents gallamine and pancuronium.
    48. (2001). Hyperactivity and intact hippocampus-dependent learning in mice lacking the M1 muscarinic acetylcholine receptor.
    49. (1991). Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies.
    50. (1998). Identification of a [3H]Ligand for the common allosteric site of muscarinic acetylcholine M2 receptors.
    51. (1994). Identification of drugs competing with dtubocurarine for an allosteric site on cardiac muscarinic receptors.
    52. (1988). Influence of ligand choice on the apparent binding profile of gallamine to cardiac muscarinic receptors. Identification of three main types of gallamine-muscarinic receptor interactions.
    53. (1969). Inhibition of the actions of carbachol and DFP on guinea pig isolated atria by alkane-bis-ammonium compounds.
    54. (2006). Interaction studies of multiple binding sites on m4 muscarinic acetylcholine receptors.
    55. (1996). Interactions of agonists with an allosteric antagonist at muscarinic acetylcholine M2 receptors.
    56. (2000). Interactions of alcuronium, TMB-8, and other allosteric ligands with muscarinic acetylcholine receptors: studies with chimeric receptors.
    57. (2003). Interactions of orthosteric and allosteric ligands with
    58. (2003). International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology.
    59. (1988). Localization of a family of muscarinic receptor mRNAs in rat brain.
    60. (1990). Localization of m5 muscarinic receptor mRNA in rat brain examined by in situ hybridization histochemistry.
    61. (2001). M5 muscarinic receptors are needed for slow activation of dopamine neurons and for rewarding brain stimulation.
    62. (1994). Mechanisms of steric and cooperative actions of alcuronium on cardiac muscarinic acetylcholine receptors.
    63. (2001). Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean.
    64. (2000). Modeling the functional effects of allosteric modulators at pharmacological receptors: An extension of the two-state model of receptor activation.
    65. (2000). Modes of allosteric interactions with free and [3H]N-methylscopolamine-occupied muscarinic M2 receptors as deduced from buffer-dependent potency shifts.
    66. (1983). Modification of the binding properties of muscarinic receptors by gallamine.
    67. (1989). Multiple in vitro interactions with and differential in vivo regulation of muscarinic receptor subtypes by tetrahydroaminoacridine.
    68. (2007). Muscarinic acetylcholine receptors in the central nervous system: structure, function, and pharmacology, in exploring the vertebrate central cholinergic nervous system.
    69. (1999). Muscarinic receptor agonists, like do-Allosteric Modulation of Muscarinic Acetylcholine Receptors Current Neuropharmacology,
    70. (1999). Muscarinic receptor subtypes involved in hippocampal circuits.
    71. (1993). Muscarinic receptors--characterization, coupling and function.
    72. (1991). Muscarinic subtype selectivity of tetrahydroaminoacridine: possible relationship to its capricious efficacy.
    73. (2003). N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity.
    74. (2005). New concepts in drug discovery: collateral efficacy and permissive antagonism.
    75. (2006). Opposing functions of spinal M2, M3, and M4 receptor subtypes in regulation of GABAergic inputs to dorsal horn neurons revealed by muscarinic receptor knockout mice.
    76. (1996). Opposite effects of alcuronium on agonist and on antagonist binding to muscarinic receptors.
    77. (1997). Pharmacological analysis of the mode of interaction of McN-A-343 at atrial muscarinic M2 receptors.
    78. (1996). Positive allosteric action of eburnamonine on cardiac muscarinic acetylcholine receptors.
    79. (1995). Positive and negative allosteric interactions on muscarinic receptors.
    80. (1990). Positive cooperativity in the binding of alcuronium and Nmethylscopolamine to muscarinic acetylcholine receptors.
    81. (1997). Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors.
    82. (1995). Potentiation by alcuronium of the antimuscarinic effect of N-methylscopolamine in guinea pig left atria.
    83. (1995). Probing of the location of the allosteric site on m1 muscarinic receptors by site-directed mutagenesis.
    84. (2006). Probing the molecular mechanism of interaction between 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine (AC-42) and the muscarinic M(1) receptor: direct pharmacological evidence that AC-42 is an allosteric agonist.
    85. (2000). Quantification of allosteric interactions at G protein-coupled Receptors using radioligand binding assays, in Current Protocols
    86. (2005). Quantitative analysis of binding parameters of [3H]Nmethylscopolamine in central nervous system of muscarinic acetylcholine receptor knockout mice. Brain Res.
    87. (2005). Regulation of M2 muscarinic acetylcholine receptor expression and signaling by prolonged exposure to allosteric modulators.
    88. (1994). Role of acidic amino acids in the allosteric modulation by gallamine of antagonist binding at the m2 muscarinic acetylcholine receptor.
    89. (1999). Site-directed mutagenesis reveals two epitopes involved in the subtype selectivity of the allosteric interactions of gallamine at muscarinic acetylcholine receptors.
    90. (1959). Some quantitative uses of drug antagonists.
    91. (2006). Structural requirements of transmembrane domain 3 for activation by the M1 muscarinic receptor agonists AC-42, AC-260584, clozapine, and N-desmethylclozapine: evidence for three distinct modes of receptor activation.
    92. (2003). Structure/activity relationships of M2 muscarinic allosteric modulators.
    93. (2002). Substituted pentacyclic carbazolones as novel muscarinic allosteric agents: synthesis and structure-affinity and cooperativity relationships.
    94. (1995). Subtype selectivity of the positive allosteric action of alcuronium at cloned M1-M5 muscarinic acetylcholine receptors.
    95. (1999). Subtype-selective positive cooperative interactions between brucine analogs and acetylcholine at muscarinic receptors: functional studies.
    96. (1998). Subtype-selective positive cooperative interactions between brucine analogues and acetylcholine at muscarinic receptors: radioligand binding studies.
    97. (1989). Tetrahydroaminoacridine and other allosteric antagonists of hippocampal M1 muscarine receptors.
    98. (2001). The allosteric interaction of otenzepad (AF-DX 116) at muscarinic M2 receptors in guinea pig atria.
    99. (1992). The autoinhibitory feedback control of acetylcholine release in human neocortex tissue.
    100. (2002). The druggable genome.
    101. (1983). The effect of McN-A-343 on muscarinic receptors in the cerebral cortex and heart.
    102. (1976). The inhibitory effect of gallamine on muscarinic receptors.
    103. (1985). The interaction of McN-A343 with pirenzepine and other selective muscarine receptor antagonists at a prejunctional muscarine receptor.
    104. (1984). The kinetics of competitive radioligand binding predicted by the law of mass action.
    105. (2003). The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys.
    106. (1936). The quantitative effects of antagonistic drugs.
    107. (2004). Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity.
    108. (1997). Three allosteric modulators act at a common site, distinct from that of competitive antagonists, at muscarinic acetylcholine M2 receptors.
    109. (1992). Two allosteric modulators interact at a common site on cardiac muscarinic receptors.
    110. (1996). Two-point kinetic experiments to quantify allosteric effects on radioligand dissociation.
    111. (1993). Use of chimeric muscarinic receptors to investigate epitopes involved in allosteric interactions.
    112. (1999). Using a radioalloster to test predictions of the cooperativity model for gallamine binding to the allosteric site of muscarinic acetylcholine M(2) receptors.

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