Skip to main content
SpringerLink
Log in

Muscarinic acetylcholine receptor modulators derived from natural toxins and diverse interaction modes

  • Reviews
  • Special Topic Chemistry for Life Sciences
  • Published:
Science China Chemistry Aims and scope Submit manuscript

Abstract

Muscarinic acetylcholine receptors (mAChRs) play crucial roles in various physiological functions and pathophysiological processes. Acetylcholine (ACh), as a classical ligand and one of the pivotal neurotransmitters, serves as a prototype for the elucidation of molecular interaction and the development of mimicked and antagonized agents. With the advances in medicinal chemistry and structural biology, more and more mAChRs modulators derived from natural toxins have been identified. Based on the chemical structures and the receptor-ligand interaction modes, these mAChRs modulators can be divided into orthosteric modulators, allosteric modulators and other modulators. Moreover, allosteric modulators can be further divided into three groups: alcuronium-like modulators, staurosporine-like modulators, and phlegmarine-like modulators. In this review, we focus on various mAChRs modulators derived from natural toxins on the basis of the receptor-ligand interaction modes. The understanding of the affinity, the intrinsic efficacy, and the selectivity of mAChRs modulators may lead to the discovery of new drug leads for the treatment of diseases related to mAChRs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Wess J. Molecular biology of muscarinic acetylcholine receptors. Crit Rev Neurobiol, 1996, 10(1): 69–99

    Article  CAS  Google Scholar 

  2. Bonner TI, Buckley NJ, Young AC, Brann MR. Identification of a family of muscarinic acetylcholine receptor genes. Science, 1987, 237(4814): 527–532

    Article  CAS  Google Scholar 

  3. Bonner TI, Young AC, Brann MR, Buckley NJ. Cloning and expression of the human and rat M5 muscarinic acetylcholine receptor genes. Neuron, 1988, 1(5): 403–410

    Article  CAS  Google Scholar 

  4. Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR. Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J Neurosci, 1991, 11(10): 3218–3226

    CAS  Google Scholar 

  5. Eglen RM. Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function. Auton Autacoid Pharmacol, 2006, 26(3): 219–233

    Article  CAS  Google Scholar 

  6. Wess J. Muscarinic acetylcholine receptor knockout mice: Novel phenotypes and clinical implications. Annu Rev Pharmacol Toxicol, 2004, 44(1): 423–450

    Article  CAS  Google Scholar 

  7. Sellin AK, Shad M, Tamminga C. Muscarinic agonists for the treatment of cognition in schizophrenia. CNS Spectrums, 2008, 13(11): 985–996

    Google Scholar 

  8. Clader JW, Wang YG. Muscarinic receptor agonists and antagonists in the treatment of Alzheimer’s disease. Curr Pharm Des, 2005, 11(26): 3353–3361

    Article  CAS  Google Scholar 

  9. Wu XJ, Chen HZ. Pharmacological and clinical studies on M1 muscarinic receptor agonist in treatment of Alzheimerdisease. Chin J Clin Pharmacol Ther, 2003, 8(5): 485–489

    Google Scholar 

  10. Abrams P, Andersson KE. Muscarinic receptor antagonists for overactive bladder. BJU Int, 2007, 100(5): 987–1006

    Article  CAS  Google Scholar 

  11. Beeh KM, Welte T, Buhl R. Anticholinergics in the treatment of chronic obstructive pulmonary disease. Respiration, 2002, 69(4): 372–379

    Article  CAS  Google Scholar 

  12. Zhang WW, Song MK, Cui YY, Wang H, Zhu L, Niu YY, Yang LM, Lu Y, Chen HZ. Differential neuropsychopharmacological influences of naturally occurring tropane alkaloids anisodamine versus scopolamine. Neurosci Lett, 2008, 443(3): 241–245

    Article  CAS  Google Scholar 

  13. Zhu X, Zhou W, Cui YY, Zhu L, Li J, Xia Z, Shao BY, Wang H, Chen HZ. Muscarinic activation attenuates abnormal processing of beta-amyloid precursor protein induced by cobalt chloride-mimetic hypoxia in retinal ganglion cells. Biochem Biophys Res Commun, 2009, 384(1): 110–113

    Article  CAS  Google Scholar 

  14. Wang H, Lu Y, Chen HZ. Differentiating effects of anisodamine on cognitive amelioration and peripheral muscarinic side effects induced by pilocarpine in mice. Neurosci Lett, 2003, 344(3): 173–176

    Article  CAS  Google Scholar 

  15. Xu GN, Yang K, Xu ZP, Zhu L, Hou LN, Qi H, Chen HZ, Cui YY. Protective effects of anisodamine on cigarette smoke extract-induced airway smooth muscle cell proliferation and tracheal contractility. Toxicol Appl Pharmacol, 2012, 262(1): 70–79

    Article  CAS  Google Scholar 

  16. Xu ZP, Wang H, Hou LN, Xia Z, Zhu LA, Chen HZ, Cui YY. Modulatory effect of anisodamine on airway hyper-reactivity and eosinophilic inflammation in a murine model of allergic asthma. Int Immunopharmacol, 2011, 11(2): 260–265

    Article  CAS  Google Scholar 

  17. Xu ZP, Yang K, Xu GN, Zhu L, Hou LN, Zhang WH, Chen HZ, Cui YY. Role of M3 mACHR in in vivo and in vitro models of Ips-induced inflammatory response. Int Immunopharmacol, 2012, 14(3): 320–327

    Article  CAS  Google Scholar 

  18. Cui Y, Devillier P, Kuang X, Wang H, Zhu L, Xu Z, Xia Z, Zemoura L, Advenier C, Chen H. Tiotropium reduction of lung inflammation in a model of chronic gastro-oesophageal reflux. Eur Respir J, 2010, 35(6): 1370–1376

    Article  CAS  Google Scholar 

  19. Zhang Y, Moreau J, Molimard M, Naline E, Bisson A, Advenier C. Contractile effect of 6 beta-acetoxy nortropane on human and guinea pig airways. Acta Pharmacol Sin, 1998, 19(3): 211–217

    CAS  Google Scholar 

  20. Zhou W, Zhu X, Zhu L, Cui YY, Wang H, Qi H, Ren QS, Chen HZ. Neuroprotection of muscarinic receptor agonist pilocarpine against glutamate-induced apoptosis in retinal neurons. Cell Mol Neurobiol, 2008, 28(2): 263–275

    Article  CAS  Google Scholar 

  21. Sheardown MJ. Muscarinic m1 receptor agonists and M2 receptor antagonists as therapeutic targets in alzheimer’s disease. Expert Opin The Pat, 2002, 12(6): 863–870

    Article  CAS  Google Scholar 

  22. Eglen RM, Choppin A, Dillon MP, Hegde S. Muscarinic receptor ligands and their therapeutic potential. Curr Opin Chem Biol, 1999, 3(4): 426–432

    Article  CAS  Google Scholar 

  23. Jakubík J, El-Fakahany EE. Allosteric modulation of muscarinic acetylcholine receptors. Pharmaceuticals, 2010, 3(9): 2838–2860

    Article  Google Scholar 

  24. Digby GJ, Shirey JK, Conn PJ. Allosteric activators of muscarinic receptors as novel approaches for treatment of CNS disorders. Molecular Biosystems, 2010, 6(8): 1345–1354

    Article  CAS  Google Scholar 

  25. Ballesteros J, Weinstein H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Meth Neurosci, 1995, 25: 366–428

    Article  CAS  Google Scholar 

  26. Hulme EC, Lu ZL, Saldanha JW, Bee MS. Structure and activation of muscarinic acetylcholine receptors. Biochem Soc Trans, 2003, 31(1): 29–34

    Article  CAS  Google Scholar 

  27. Hulme EC, Curtis CaM, Page KM, Jones PG. The role of charge interactions in muscarinic agonist binding, and receptor-response coupling. Life Sci, 1995, 56(11–12): 891–898

    Article  CAS  Google Scholar 

  28. Han SJ. Identification of an agonist-induced conformational change occurring adjacent to the ligand-binding pocket of the M3 muscarinic acetylcholine receptor. J Biol Chem, 2005, 280(41): 34849–34858

    Article  CAS  Google Scholar 

  29. Allman K, Page KM, Curtis CaM, Hulme EC. Scanning mutagenesis identifies amino acid side chains in transmembrane domain 5 of the M-1 muscarinic receptor that participate in binding the acetyl methyl group of acetylcholine. Mol Pharmacol, 2000, 58(1): 175–184

    CAS  Google Scholar 

  30. Valant C, Gregory KJ, Hall NE, Scammells PJ, Lew MJ, Sexton PM, Christopoulos A. A novel mechanism of G protein-coupled receptor functional selectivity muscarinic partial agonist MCN-A-343 as a bitopic orthosteric/allosteric ligand. J Biol Chem, 2008, 283(43): 29312–29321

    Article  CAS  Google Scholar 

  31. Leppik RA, Miller RC, Eck M, Paquet JL. Role of acidic amino-acids in the allosteric modulation by gallamine of antagonist binding at the M2 muscarinic acetylcholine-receptor. Mol Pharmacol, 1994, 45(5): 983–990

    CAS  Google Scholar 

  32. Huang XP, Prilla S, Mohr K, Ellis J. Critical amino acid residues of the common allosteric site on the M-2 muscarinic acetylcholine receptor: More similarities than differences between the structurally divergent agents gallamine and bis(ammonio) alkane-type hexamethylene-bis dimethyl-(3-phthalimidopropyl)ammonium dibromide. Mol Pharmacol, 2005, 68(3): 769–778

    CAS  Google Scholar 

  33. Voigtlander U, Johren K, Mohr M, Raasch A, Trankle C, Buller S, Ellis J, Holtje HD, Mohr K. Allosteric site on muscarinic acetylcholine receptors: Identification of two amino acids in the muscarinic M-2 receptor that account entirely for the M-2/M-5 subtype selectivities of some structurally diverse allosteric ligands in n-methylscopolamine-occupied receptors. Mol Pharmacol, 2003, 64(1): 21–31

    Article  Google Scholar 

  34. May LT, Avlani VA, Langmead CJ, Herdon HJ, Wood MD, Sexton PM, Christopoulos A. Structure-function studies of allosteric agonism at M2 muscarinic acetylcholine receptors. Mol Pharmacol, 2007, 72(2): 463–476

    Article  CAS  Google Scholar 

  35. Lebon G, Langmead CJ, Tehan BG, Hulme EC. Mutagenic mapping suggests a novel binding mode for selective agonists of M-1 muscarinic acetylcholine receptors. Mol Pharmacol, 2009, 75(2): 331–341

    Article  CAS  Google Scholar 

  36. Vistoli G, Pedretti A, Dei S, Scapecchi S, Marconi C, Romanelli MN. Docking analyses on human muscarinic receptors: Unveiling the subtypes peculiarities in agonists binding. Biorg Med Chem, 2008, 16(6): 3049–3058

    Article  CAS  Google Scholar 

  37. Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: From structure to function. Physiol Rev, 2009, 89(1): 73–120

    Article  CAS  Google Scholar 

  38. Lindström L, Meyerson B. The effect of pilocarpine, oxotremorine and arecoline in combination with methyl-atropine or atropine on hormone activated oestrous behaviour in ovariectomized rats. Psychopharmacologia, 1967, 11(5): 405–413

    Article  Google Scholar 

  39. Haubrich DR, Reid WD. Effects of pilocarpine or arecoline administration on acetylcholine levels and serotonin turnover in rat brain. J Pharmacol Exp Ther, 1972, 181(1): 19–27

    CAS  Google Scholar 

  40. Thomas RL, Langmead CJ, Wood MD, Challiss RJ. Contrasting effects of allosteric and orthosteric agonists on M1 muscarinic acetylcholine receptor internalization and down-regulation. J Pharmacol Exp Ther, 2009, 331(3): 1086–1095

    Article  CAS  Google Scholar 

  41. Fisher A. Muscarinic receptor agonists in Alzheimer’s disease — more than just symptomatic treatment? CNS Drugs, 1999, 12(3): 197–214

    Article  CAS  Google Scholar 

  42. Niu YY, Zhu L, Cui YY, Liu HZ, Chen HZ, Lu Y. The absolute configuration plays an important role in muscarinic activity of BGT-A and its analogs. Biorg Med Chem, 2008, 16(24): 10251–10256

    Article  CAS  Google Scholar 

  43. Niu YY, Yang LM, Cui YY, Zhu L, Feng JM, Chen HZ, Lu Y. Synthesis and bioactivities of 3alpha-substituted-6betaacetoxytropane derivatives. Chemical World, 2005, 46(5): 299–301

    CAS  Google Scholar 

  44. Yang LM, Niu YY, Zhu L, Xie YF, Gu YF. Cui YY, Chen HZ, Lu Y. Structure modification and structure-activity relationship of anisodamine. Chin Pharm J, 2008, 43(7): 496–498

    CAS  Google Scholar 

  45. Liu HZ, Cui YY, Niu YY, Feng JM, Chen HZ, Lu Y. Synthesis and biological activity of tropane derivatives. Chin Pharm J, 2007, 42(14): 1112–1115

    CAS  Google Scholar 

  46. Cui YY, Feng JM, Liu HZ, Sun YY, Rong ZX, Lu Y, Chen HZ. Effects of newly synthesized nortropane derivatives on muscarinic-receptors in guinea pig ileum. Acta Universitatis Medicinalis Secondae Shanghai, 2000, 20(1): 22–24

    CAS  Google Scholar 

  47. Cui YY, Feng JM, Liu HZ, Zhu L, Rong ZX, Lu Y, Chen HZ. Effect of a novel muscarinic receptor agonist MA9701 on cognitive improvement. Chin J Clin Pharmacol Ther, 2003, 8(5): 503–505

    Google Scholar 

  48. Zhu L, Yang LM, Cui YY, Zheng PL, Niu YY, Wang H, Lu Y, Ren QS, Wei PJ, Chen HZ. Stereoselectivity of satropane, a novel tropane analog, on iris muscarinic receptor activation and intraocular hypotension. Acta Pharmacol Sin, 2008, 29(2): 177–184

    Article  Google Scholar 

  49. Liu H, Ou M, Yan Z, Zhu L, Cui Y, Niu Y, Chen H, Lu Y. Synthesis of tropane compounds and their antagonistic activity and tissue selectivity to trachea of rats. Journal of Shanghai Jiaotong University, Medical Science, 2012, 32(1): 27–31

    Google Scholar 

  50. Niu YY, Yang LM, Deng KM, Yao JH, Zhu L, Chen CY, Zhang M, Zhou JE, Shen TX, Chen HZ, Lu Y. Quantitative structure-selectivity relationship for M2 selectivity between M1 and M2 of piperidinyl piperidine derivatives as muscarinic antagonists. Bioorg Med Chem Lett, 2007, 17(8): 2260–2266

    Article  CAS  Google Scholar 

  51. Niu YY, Yang LM, Liu HZ, Cui YY, Zhu L, Feng JM, Yao JH, Chen HZ, Fan BT, Chen ZN, Lu Y. Activity and QSAR study of Baogongteng A and its derivatives as muscarinic agonists. Bioorg Med Chem Lett, 2005, 15(21): 4814–4818

    Article  CAS  Google Scholar 

  52. Wang ZP, Liu HZ, Zhu L, Hu YM, Cui YY, Niu YY, Lu Y, Chen HZ. The effect of absolute configuration on activity, subtype selectivity (M3/M2) of 3 alpha-acyloxy-6 beta-acetoxyltropane derivatives as muscarinic M3 receptor antagonists. Biorg Med Chem, 2013, 21(5): 1234–1239

    Article  CAS  Google Scholar 

  53. Fraser CM, Wang CD, Robinson DA, Gocayne JD, Venter JC. Site-directed mutagenesis of m1 muscarinic acetylcholine-receptors—conserved aspartic acids play important roles in receptor function. Mol Pharmacol, 1989, 36(6): 840–847

    CAS  Google Scholar 

  54. Schwarz RD, Spencer CJ, Jaen JC, Mirzadegan T, Moreland D, Tecle H, Thomas AJ. Mutations of Aspartate-103 in the HM2 receptor and alterations in receptor-binding properties of muscarinic agonists. Life Sci, 1995, 56(11–12): 923–929

    Article  CAS  Google Scholar 

  55. Huang XP, Nagy PI, Williams FE, Peseckis SM, Messer WS. Roles of Threonine 192 and Asparagine 382 in agonist and antagonist interactions with M-1 muscarinic receptors. Br J Pharmacol, 1999, 126(3): 735–745

    Article  CAS  Google Scholar 

  56. Heitz F, Holzwarth JA, Gies JP, Pruss RM, Trumpp-Kallmeyer S, Hibert MF, Guenet C. Site-directed mutagenesis of the putative human muscarinic M-2 receptor binding site. Eur J Pharmacol, 1999, 380(2–3): 183–195

    Article  CAS  Google Scholar 

  57. Vogel WK, Peterson GL, Broderick DJ, Mosser VA, Schimerlik MI. Double mutant cycle analysis of Aspartate 69, 97, and 103 to Asparagine mutants in the M2 muscarinic acetylcholine receptor. Arch Biochem Biophys, 1999, 361(2): 283–294

    Article  CAS  Google Scholar 

  58. Jakubik J, El-Fakahany EE, Tucek S. Evidence for a tandem two-site model of ligand binding to muscarinic acetylcholine receptors. J Biol Chem, 2000, 275(25): 18836–18844

    Article  CAS  Google Scholar 

  59. Goodwin JA, Hulme EC, Langmead CJ, Tehan BG. Roof and floor of the muscarinic binding pocket: Variations in the binding modes of orthosteric ligands. Mol Pharmacol, 2007, 72(6): 1484–1496

    Article  CAS  Google Scholar 

  60. Christopoulos A, Pierce TL, Sorman JL, El-Fakahany EE. On the unique binding and activating properties of xanomeline at the M-1 muscarinic acetylcholine receptor. Mol Pharmacol, 1998, 53(6): 1120–1130

    CAS  Google Scholar 

  61. Jakubik J, Tucek S, El-Fakahany EE. Allosteric modulation by persistent binding of xanomeline of the interaction of competitive ligands with the M-1 muscarinic acetylcholine receptor. J Pharmacol Exp Ther, 2002, 301(3): 1033–1041

    Article  CAS  Google Scholar 

  62. Jakubik J, Tucek S, El-Fakahany EE. Role of receptor protein and membrane lipids in xanomeline wash-resistant binding to muscarinic M-1 receptors. J Pharmacol Exp Ther, 2004, 308(1): 105–110

    Article  CAS  Google Scholar 

  63. Kane BE, Grant MKO, El-Fakahany EE, Ferguson DM. Synthesis and evaluation of xanomeline analogs—Probing the wash-resistant phenomenon at the M-1 muscarinic acetylcholine receptor. Biorg Med Chem, 2008, 16(3): 1376–1392

    Article  CAS  Google Scholar 

  64. De Lorme KC, Sikorski KL, Grant MKO, El-Fakahany EE. Long-term wash-resistant effects of brief interaction of xanomeline at the M-1 muscarinic receptor. Neurosci Lett, 2006, 410(1): 11–14

    Article  Google Scholar 

  65. Kruse AC, Hu J, Pan AC, Arlow DH, Rosenbaum DM, Rosemond E, Green HF, Liu T, Chae PS, Dror RO. Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature, 2012, 482(7386): 552–556

    Article  CAS  Google Scholar 

  66. Haga K, Kruse AC, Asada H, Yurugi-Kobayashi T, Shiroishi M, Zhang C, Weis WI, Okada T, Kobilka BK, Haga T. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature, 2012, 482(7386): 547–551

    Article  CAS  Google Scholar 

  67. Kenakin TP. Ligand detection in the allosteric world. J Biomol Screen, 2010, 15(2): 119–130

    Article  CAS  Google Scholar 

  68. Christopoulos A. Allosteric binding sites on cell-surface receptors: Novel targets for drug discovery. Nat Rev Drug Discov, 2002, 1(3): 198–210

    Article  CAS  Google Scholar 

  69. Ellis J, Huyler J, Brann MR. Allosteric regulation of cloned M1-M5 muscarinic receptor subtypes. Biochem Pharmacol, 1991, 42(10): 1927–1932

    Article  CAS  Google Scholar 

  70. Trankle C, Kostenis E, Mohr K. Muscarinic allosteric modulation: M-2/M-3 subtype selectivity of gallamine is independent of g-protein coupling specificity. Naunyn-Schmiedeberg’s Arch Pharmacol, 2001, 364(2): 172–178

    Article  CAS  Google Scholar 

  71. Krejci A, Tucek S. Changes of cooperativity between n-methylscopolamine and allosteric modulators alcuronium and gallamine induced by mutations of external loops of muscarinic M-3 receptors. Mol Pharmacol, 2001, 60(4): 761–767

    CAS  Google Scholar 

  72. Ellis J, Seidenberg M. Interactions of alcuronium, TMB-8, and other allosteric ligands with muscarinic acetylcholine receptors: Studies with chimeric receptors. Mol Pharmacol, 2000, 58(6): 1451–1460

    CAS  Google Scholar 

  73. Gnagey AL, Seidenberg M, Ellis J. Site-directed mutagenesis reveals two epitopes involved in the subtype selectivity of the allosteric interactions of gallamine at muscarinic acetylcholine receptors. Mol Pharmacol, 1999, 56(6): 1245–1253

    CAS  Google Scholar 

  74. Buller S, Zlotos DP, Mohr K, Ellis J. 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. Mol Pharmacol, 2002, 61(1): 160–168

    Article  CAS  Google Scholar 

  75. Johren K, Holtje HD. A model of the human M-2 muscarinic acetylcholine receptor. J Comput-Aided Mol Des, 2002, 16(11): 795–801

    Article  Google Scholar 

  76. Jakubik J, Krejci A, Dolezal V. Asparagine, valine, and threonine in the third extracellular loop of muscarinic receptor have essential roles in the positive cooperativity of strychnine-like allosteric modulators. J Pharmacol Exp Ther, 2005, 313(2): 688–696

    Article  CAS  Google Scholar 

  77. Prilla S, Schrobang J, Ellis J, Holtje HD, Mohr K. Allosteric interactions with muscarinic acetylcholine receptors: Complex role of the conserved tryptophan M-2 (422)Trp in a critical cluster of amino acids for baseline affinity, subtype selectivity, and cooperativity. Mol Pharmacol, 2006, 70(1): 181–193

    CAS  Google Scholar 

  78. Lazareno S, Popham A, Birdsall NJM. Analogs of WIN 62,577 define a second allosteric site on muscarinic receptors. Mol Pharmacol, 2002, 62(6): 1492–1505

    Article  CAS  Google Scholar 

  79. Lanzafame AA, Sexton PM, Christopoulos A. Interaction studies of multiple binding sites on M-4 muscarinic acetylcholine receptors. Mol Pharmacol, 2006, 70(2): 736–746

    Article  CAS  Google Scholar 

  80. Spalding TA, Trotter C, Skjaerbaek N, Messier TL, Currier EA, Burstein ES, Li DH, Hacksell U, Brann MR. Discovery of an ectopic activation site on the M-1 muscarinic receptor. Mol Pharmacol, 2002, 61(6): 1297–1302

    Article  CAS  Google Scholar 

  81. Langmead CJ, Austin NE, Branch CL, Brown JT, Buchanan KA, Davies CH, Forbes IT, Fry VaH, Hagan JJ, Herdon HJ, Jones GA, Jeggo R, Kew JNC, Mazzali A, Melarange R, Patel N, Pardoe J, Randall AD, Roberts C, Roopun A, Starr KR, Teriakidis A, Wood MD, Whittington M, Wu Z, Watson J. Characterization of a cns penetrant, selective M-1 muscarinic receptor agonist, 77-LH-28-1. Br J Pharmacol, 2008, 154(5): 1104–1115

    Article  CAS  Google Scholar 

  82. Thomas RL, Langmead CJ, Wood MD, Challiss RaJ. Contrasting effects of allosteric and orthosteric agonists on M-1 muscarinic acetylcholine receptor internalization and down-regulation. J Pharmacol Exp Ther, 2009, 331(3): 1086–1095

    Article  CAS  Google Scholar 

  83. Chen Y G, Liu Y J, Jiang J H, Liu B. New progress in the study of lycopodium alkaloids. Journal of Yunnan Normal University (Natural Sciences Edition), 2010, 30(6): 12–24

    Google Scholar 

  84. Tan C H, Zhu D Y. Progress in the research of lycopodium alkaloids. Chin J Nat Med, 2003, 1(1): 1–7

    CAS  Google Scholar 

  85. Spalding TA, Ma JN, Ott TR, Friberg M, Bajpai A, Bradley SR, Davis RE, Brann MR, Burstein ES. Structural requirements of transmembrane domain 3 for activation by the M-1 muscarinic receptor agonists AC-42, AC-260584, Clozapine, and N-desmethylclozapine: Evidence for three distinct modes of receptor activation. Mol Pharmacol, 2006, 70(6): 1974–1983

    Article  CAS  Google Scholar 

  86. Avlani VA, Langmead CJ, Guida E, Wood MD, Tehan BG, Herdon HJ, Watson JM, Sexton PM, Christopoulos A. Orthosteric and allosteric modes of interaction of novel selective agonists of the M-1 muscarinic acetylcholine receptor. Mol Pharmacol, 2010, 78(1): 94–104

    Article  CAS  Google Scholar 

  87. Gregory KJ, Hall NE, Tobin AB, Sexton PM, Christopoulos A. Identification of orthosteric and allosteric site mutations in M2 muscarinic acetylcholine receptors that contribute to ligand-selective signaling bias. J Biol Chem, 2010, 285(10): 7459–7474

    Article  CAS  Google Scholar 

  88. Marquer C, Fruchart-Gaillard C, Letellier G, Marcon E, Mourier G, Zinn-Justin S, Menez A, Servent D, Gilquin B. Structural model of ligand-G protein-coupled receptor (GPCR) complex based on experimental double mutant cycle data MT7 snake toxin bound to dimeric HM1 muscarinic receptor. J Biol Chem, 2011, 286(36): 31661–31675

    Article  CAS  Google Scholar 

  89. Xu J, Xu J, Chen H. Interpreting the structural mechanism of action for MT7 and human muscarinic acetylcholine receptor 1 complex by modeling protein-protein interaction. J Biomol Struct Dyn, 2012, 30(1): 30–44

    Article  Google Scholar 

  90. Servent D, Fruchart-Gaillard C. Muscarinic toxins: Tools for the study of the pharmacological and functional properties of muscarinic receptors. J Neurochem, 2009, 109(5): 1193–1202

    Article  CAS  Google Scholar 

  91. Adem A, Asblom A, Johansson G, Mbugua PM, Karlsson E. Toxins from the venom of the green mamba dendroaspis-angusticeps that inhibit the binding of quinuclidinyl benzilate to muscarinic acetylcholine-receptors. Biochim Biophys Acta, 1988, 968(3): 340–345

    Article  CAS  Google Scholar 

  92. Bradley KN. Muscarinic toxins from the green mamba. Pharmacol Ther, 2000, 85(2): 87–109

    Article  CAS  Google Scholar 

  93. Karlsson E, Jolkkonen M, Mulugeta E, Onali P, Adem A. Snake toxins with high selectivity for subtypes of muscarinic acetylcholine receptors. Biochimie, 2000, 82(9–10): 793–806

    Article  CAS  Google Scholar 

  94. Karlsson E, Jolkkonen M, Satyapan N, Adem A, Kumlin E, Hellman U, Wernstedt C. Protein toxins that bind to muscarinic acetylcholine-receptors. Toxins and Exocytosis, 1994, 710(1): 153–161

    CAS  Google Scholar 

  95. Max SI, Liang JS, Valentine HH, Potter LT. Use of m1-toxin as a selective antagonist of M1-muscarinic receptors. J Pharmacol Exp Ther, 1993, 267(1): 480–485

    CAS  Google Scholar 

  96. Jolkkonen M. Muscarinic toxins from dendroaspis (mamba) venom: Peptides selective for subtypes of muscarinic acetylcholine receptors. 1996, 1–51

    Google Scholar 

  97. Fruchart-Gaillard C, Mourier G, Marquer C, Menez A, Servent D. Identification of various allosteric interaction sites on M-1 muscarinic receptor using I-125-MET35-oxidized muscarinic toxin 7. Mol Pharmacol, 2006, 69(5): 1641–1651

    Article  CAS  Google Scholar 

  98. Krajewski JL, Dickerson IM, Potter LT. Site-directed mutagenesis of M1-toxin1: Two amino acids responsible for stable toxin binding to m-1 muscarinic receptors. Mol Pharmacol, 2001, 60(4): 725–731

    CAS  Google Scholar 

  99. Mourier G, Dutertre E, Fruchart-Gaillard C, Menez A, Servent D. Chemical synthesis of MT1 and MT7 muscarinic toxins: Critical role of Arg-34 in their interaction with M-1 muscarinic receptor. Mol Pharmacol, 2003, 63(1): 26–35

    Article  CAS  Google Scholar 

  100. Kukkonen A, Perakyla M, Akerman KEO, Nasman J. Muscarinic toxin 7 selectivity is dictated by extracellular receptor loops. J Biol Chem, 2004, 279(49): 50923–50929 Fruchart-Gaillard C, Mourier G, Marquer C, Stura E, Birdsall NJM, Servent D. Different interactions between MT7 toxin and the human muscarinic M-1 receptor in its free and N-methylscopolamine-occupied states. Mol Pharmacol, 2008, 74 (6): 1554–1563

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Institute of Medical Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    JianRong Xu, Hao Wang & HongZhuan Chen

Authors
  1. JianRong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. HongZhuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to HongZhuan Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, J., Wang, H. & Chen, H. Muscarinic acetylcholine receptor modulators derived from natural toxins and diverse interaction modes. Sci. China Chem. 56, 1333–1343 (2013). https://doi.org/10.1007/s11426-013-4958-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11426-013-4958-x

Keywords

Search

Navigation