CNS Drugs

, Volume 12, Issue 3, pp 197–214 | Cite as

Muscarinic Receptor Agonists in Alzheimer’s Disease

More Than Just Symptomatic Treatment?
  • Abraham FisherEmail author
Review Article


Research into and development of selective muscarinic receptor agonists for the treatment of Alzheimer’s disease is based on the ‘cholinergic hypothesis’ of the disease. This implies that cholinergic replacement therapy might be beneficial in alleviating some of the cognitive dysfunctions associated with the disorder. Muscarinic M1 receptor—selective agonists may be effective in the treatment of Alzheimer’s disease, regardless of the extent of degeneration of presynaptic cholinergic projections to the frontal cortex and hippocampus. In this context, such compounds represent a more rational treatment for Alzheimer’s disease than the cholinesterase inhibitors.

However, disappointing clinical results have been reported with some muscarinic agonists in patients with Alzheimer’s disease. This may be due to a lack of selectivity for M1 receptors (as is the case with milameline), low intrinsic activity (Lu 25109), very low bioavailability and extensive metabolism (xanomeline), and a narrow safety margin [all of the abovementioned drugs and sabcomeline (SB 202026)].

Recent studies indicate a relationship between the formation of β-amyloid plaques and neurofibrillary tangles and the loss of cholinergic function in the brains of patients who had had Alzheimer’s disease. A cholinergic hypofunction in Alzheimer’s disease can be linked to the formation of neurotoxic β-amyloids, which can further decrease the release of acetylcholine (a presynaptic effect) and impair the coupling of M1 receptors with G-proteins (a postsynaptic effect). This uncoupling leads to decreased signal transduction, impairments in cognition, a reduction in the levels of trophic-secreted amyloid precursor proteins, the generation of more neurotoxic β-amyloids and a further decrease in acetylcholine release. This ‘vicious cycle’ may be prevented, in principle, by M1-selective agonists.

These new findings raise the exciting prospect that future M1 agonists may be useful both as symptomatic treatments (e.g. to treat cognitive and behavioural symptoms) and as disease-modifying agents in Alzheimer’s disease.


Adis International Limited Muscarinic Receptor AChE Inhibitor Muscarinic Agonist Muscarinic Receptor Subtype 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Court JA, Perry EK. Dementia: the neurochemical basis of putative transmitter orientated therapy. Pharmac Ther 1991; 52: 423–43Google Scholar
  2. 2.
    Fisher A, Barak D. Progress and perspectives in new muscarinic agonists. Drug News Perspectives 1994; 7: 453–64Google Scholar
  3. 3.
    Simonson W. Promising agents for treating Alzheimer’s disease. Am J Health Cyst Pharm 1998; 55: S11–S16Google Scholar
  4. 4.
    Spencer CM, Noble S. Rivastigmine: a review of its use in Alzheimer’s disease. Drugs Aging 1998; 13: 391–411PubMedGoogle Scholar
  5. 5.
    Cummings JL, Vinters HV, Cole GM, et al. Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology 1998; 51: S2–S17PubMedGoogle Scholar
  6. 6.
    Giacobini E. From molecular structure to Alzheimer therapy. Jap J Pharmacol 1997; 74: 225–41PubMedGoogle Scholar
  7. 7.
    Pavia J, de Ceballos ML, de la Cuesta FS. Alzheimer’s disease: relationship between muscarinic cholinergic receptors, beta-amyloid and tau proteins. Fundam Clin Pharmacol 1998; 12: 473–81PubMedGoogle Scholar
  8. 8.
    Avery EE, Baker LD, Asthana S, et al. Potential role of muscarinic agonists in Alzheimer’s disease. Drugs Aging 1997; 11: 450–9PubMedGoogle Scholar
  9. 9.
    Eglen RM, Hegde SS. Muscarinic receptor subtypes: pharmacology and therapeutic potential. DN&P 1997; 10: 462–9Google Scholar
  10. 10.
    Fisher A. Muscarinic agonists for the treatment of Alzheimer’s disease: progress and perspectives. Exp Opin Invest Drugs 1997; 6: 1395–411Google Scholar
  11. 11.
    Wulfert E. Treatment development strategies for Alzheimer’s disease. CNS Drug Rev 1996; 2: 238–55Google Scholar
  12. 12.
    Emmerling MR, Schwarz RD, Spiegel K, et al. New perspectives on developing muscarinic agonists for treating Alzheimer’s disease [database]. Alzheimer’s Dis 1997; 2 (4)Google Scholar
  13. 13.
    Svensson AL, Alafuzoff I, Nordberg A. Characterization of muscarinic receptor subtypes in Alzheimer and control brain cortices by selective muscarinic antagonists. Brain Res 1992; 596: 142–8PubMedGoogle Scholar
  14. 14.
    Fisher A, editor. Muscarinic agonists and Alzheimer’s disease. Austin (TX): RG Landes Company, Medical Intelligence Unit, 1996Google Scholar
  15. 15.
    Harrison PJ, Barton AJL, McDonald B, et al. Alzheimer’s disease: specific increases in a G-protein subunit (Gsα) mRNA in hippocampal and cortical neurons. Mol Brain Res 1991; 10: 71–81PubMedGoogle Scholar
  16. 16.
    Gurwitz D, Haring R, Heldman E, et al. Discrete activation of transduction pathways associated with acetylcholine M1 receptor by several muscarinic ligands. Eur J Pharmacol (Mol Pharmacol) 1994; 267: 21–31Google Scholar
  17. 17.
    Nitsch RN, Slack BE, Wurtman RJ, et al. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 1992; 258: 304–7PubMedGoogle Scholar
  18. 18.
    Bowen DM, Francis PT, Chessell IP, et al. Neurotransmission — the link integrating Alzheimer research? TINS 1994; 17: 149–50PubMedGoogle Scholar
  19. 19.
    Buxbaum JD, Oishi M, Chen HI, et al. Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer β/A4 amyloid protein precursor. Proc Natl Acad Sci U S A 1992; 89: 10075–8PubMedGoogle Scholar
  20. 20.
    Lahiri DK, Nall C, Farlow MR. The cholinergic agonist carbachol reduces intracellular β-amyloid precursor protein in PC12 and C6 cells. Biochem Int 1992; 28: 853–60PubMedGoogle Scholar
  21. 21.
    Haring R, Gurwitz D, Barg J, et al. Amyloid precursor protein secretion via muscarinic receptors: reduced desensitization using the M1-selective agonist AF102B. Biochem Biophys Res Comm 1994; 203: 652–8PubMedGoogle Scholar
  22. 22.
    Eckols K, Bymaster FP, Mitch CH, et al. The muscarinic M1 agonist xanomeline increases soluble amyloid precursor protein release from CHO M1 cells. Life Sci 1995; 57: 1183–90PubMedGoogle Scholar
  23. 23.
    Haring H, Fisher A, Marciano D, et al. Mitogen-activated kinase-dependent and protein kinase C-dependent pathways link the M1 muscarinic receptor to β-amyloid precursor protein secretion. J Neurochem 1998; 71: 2094–103PubMedGoogle Scholar
  24. 24.
    Hung AY, Haass C, Nitsch RT, et al. Activation of protein kinase C inhibits cellular production of the amyloid β-protein. J Biolog Chem 1993; 268: 22959–62Google Scholar
  25. 25.
    Wolf BA, Werfkin AM, Jolly YC, et al. Muscarinic regulation of Alzheimer’s disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells. J Biol Chem 1995; 270: 4916–22PubMedGoogle Scholar
  26. 26.
    Checler F. Processing of the β-Amyloid precursor protein and its regulation in Alzheimer’s disease. J Neurochem 1995; 65: 1431–44PubMedGoogle Scholar
  27. 27.
    Pinkas-Kramarski R, Stein R, Lindenboim L, et al. Growth factor-like effects mediated by muscarinic receptors in PC12M1 cells. J Neurochem 1992; 59: 2158–66PubMedGoogle Scholar
  28. 28.
    Gurwitz D, Haring R, Pinkas-Kramarski R, et al. NGF-dependent neurotrophic-like effects of AF102B, an M1 muscarinic agonist, in PC12M1 cells. NeuroReport 1995; 6: 485–8PubMedGoogle Scholar
  29. 29.
    Mount HTJ, Dreyfus CF, Black IB, et al. Muscarinic stimulation promotes cultured Purkinje cell survival: a role for acetylcholine in cerebellar development? J Neurochem 1994; 63: 2065–73PubMedGoogle Scholar
  30. 30.
    Alberch J, Gurwitz D, Fisher A, et al. Novel muscarinic M1 receptor agonists promote survival of CNS neurons in primary cell culture. Soc Neurosci Abstr 1995; 21: 2040Google Scholar
  31. 31.
    Haring R, Gurwitz D, Barg J, et al. NGF promotes amyloid protein secretion via muscarinic receptor activation. Biochem Biophys Res Comm 1995; 213: 15–23PubMedGoogle Scholar
  32. 32.
    Sadot E, Gurwitz D, Barg J, et al. Activation of M1-muscarinic acetylcholine receptor regulates tau phosphorylation in transfected PC12 cells. J Neurochem 1996; 66: 877–80PubMedGoogle Scholar
  33. 33.
    Forlenza O, Spink J, Oleson O, et al. Muscarinic agonists reduce tau phosphorylation in transfected cells and in neurons [abstract]. Neurobiol Aging 1998; 19: S218Google Scholar
  34. 34.
    Genis I, Fisher A, Michaelson DM. Site-specific dephosphorylation of tau of apolipoprotein E-deficient and control mice by M1 muscarinic agonist treatment. J Neurochem 1999; 12(1): 206–13Google Scholar
  35. 35.
    Lindenboim L, Pinkas-Kramarski R, Sokolovsky M, et al. Activation of muscarinic receptors inhibits apoptosis in PC12M1 cells. J Neurochem 1995; 64: 2491–9PubMedGoogle Scholar
  36. 36.
    von der Kammer H, Mayhaus M, Albrecht C, et al. Muscarinic acetylcholine receptors activate expression of the Egr gene family of transcription factors. J Biolog Chem 1998; 273(23): 14538–44Google Scholar
  37. 37.
    Nitsch RM, Rossner S, Albrecht C, et al. Muscarinic acetylcholine receptors activate the acetylcholinesterase gene promoter. J Physiol (Paris) 1998; 92(3–4): 257–64Google Scholar
  38. 38.
    Schwarz RD. Muscarinic receptor agonists under development for the treatment of Alzheimer’s disease. Alzheimer’s Dis 1997; 2: 459–65Google Scholar
  39. 39.
    Parnetti L, Senin U, Mecocci P. Cognitive enhancement therapy for Alzheimer’s disease. Drugs 1997; 53: 752–68PubMedGoogle Scholar
  40. 40.
    Eglen RM, Watson N. Selective muscarinic receptor agonists and antagonists. Pharmacol Toxicol 1996; 78: 59–8PubMedGoogle Scholar
  41. 41.
    Moltzen EK, Bjornholm B. Medicinal chemistry of muscarinic agonists: developments since 1990. Drugs Future 1995; 20: 37–54Google Scholar
  42. 42.
    Hulme EC, Birdsall NJM, Buckley NJ. Muscarinic receptor subtypes. Ann Rev Pharmacol Toxicol 1990; 30: 633–73Google Scholar
  43. 43.
    Caulfield MP, Birdsall NJM. International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors 1998; 50(2): 279–90Google Scholar
  44. 44.
    Bymaster EP, Shannon HE, Mitch CH, et al. Xanomeline: pre-clinical and clinical pharmacology of an M1 muscarinic agonist. In: Fisher A, editor. Muscarinic agonists and Alzheimer’s disease. Austin (TX): RG Landes Company, Medical Intelligence Unit, 1996: 155–84Google Scholar
  45. 45.
    Falcone JF, Bymaster FP, Butler T, et al. Determination of the intrinsic functional muscarinic activity of xanomeline. Subtypes of muscarinic receptors. 8th International Symposium; 1998 Aug 25–29; Danvers (MA), USAGoogle Scholar
  46. 46.
    Bymaster FP, Whitesitt CA, Shannon HE, et al. Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer’s disease. Drug Develop Res 1997; 40: 158–70Google Scholar
  47. 47.
    Freedman SB, Patel S, Harley EA, et al. L-687,306: a functionally selective and potent muscarinic M1 receptor agonist. Eur J Pharmacol 1992; 215: 135–6PubMedGoogle Scholar
  48. 48.
    Freedman SB, Dawson GR, Iversen LL, et al. The design of novel muscarinic partial agonists that have functional selectivity in pharmacological preparations in vitro and reduced side-effect profile in vitro and reduced side-effect profile in vivo. Life Sci 1993; 52: 489–95PubMedGoogle Scholar
  49. 49.
    Meier E, Frederiksen K, Nielsen M, et al. Pharmacological in vitro characterization of the arecoline bioisostere, Lu 25-109-T, a muscarinic compound with M1-agonistic and M2/M3-antagonistic properties. Drug Develop Res 1997; 40: 1–16Google Scholar
  50. 50.
    Muller D, Wiegmann H, Langer U, et al. Lu 25-109, a combined ml agonist and m2 antagonist, modulates regulated processing of the amyloid precursor protein of Alzheimer’s disease. J Neural Transm 1998; 105: 1029–43PubMedGoogle Scholar
  51. 51.
    Heisterberg J, Forrest M. Lu 25-109 — a new muscarinic agent. Neurobiol Aging 1996; Suppl. 17: S139Google Scholar
  52. 52.
    Sramek JJ, Forrest M, Mengel H, et al. A bridging study of LU 25-109 in patients with probable Alzheimer’s disease. Life Sci 1998; 62: 195–202PubMedGoogle Scholar
  53. 53.
    Forest’s M1 agonist in Alzheimer’s disease fails. SCRIP 1998 Aug 26: 16Google Scholar
  54. 54.
    Davis R, Raby C, Callahan MJ, et al. Subtype selective muscarinic agonists: potential therapeutic agents for Alzheimer’s disease. Prog Brain Res 1993; 98: 439–45PubMedGoogle Scholar
  55. 55.
    Tecle H, Lauffer DJ, Mirzadegan T, et al. Synthesis and SAR of bulky 1-azabicyclo[2.2.1]-3-one oximes as muscarinic receptor subtype selective agonists. Life Sci 1993; 52: 505–11PubMedGoogle Scholar
  56. 56.
    Jaen J, Barrett S, Brann M, et al. In vitro and in vivo evaluation of the subtype-selective muscarinic agonist PD 151832. Life Sci 1995; 56: 845–52PubMedGoogle Scholar
  57. 57.
    Messer WS Jr, Abuh YF, Ryan K, et al. Tetrahydropyrimidine derivatives display functional selectivity for M1 muscarinic receptors in brain. Drug Develop Res 1997; 40: 171–84Google Scholar
  58. 58.
    Shapiro G, Floersheim P, Boelsterli J, et al. Muscarinic activity of the thiolactone, lactam, lactol and thio analogues of pilocarpine and a hypothetical model for the binding of agonists to the M1 receptors. J Med Chem 1992; 35: 15–27PubMedGoogle Scholar
  59. 59.
    Enz A, Boddeke H, Sauter A, et al. SDZ ENS 163 a novel pilocarpine like drug: pharmacological in vitro and in vivo profile. Life Sci 1993; 52(5–6): 513–20PubMedGoogle Scholar
  60. 60.
    Wanibuchi F, Konishi T, Harada M, et al. Pharmacological studies on novel muscarinic agonists, 1-oxa-8-azaspiro[4.5]decane derivatives, YM796 and YM 954. Eur J Pharmacol 1990; 187: 479–86PubMedGoogle Scholar
  61. 61.
    Wu ES, Kover A. Spiro-ixoazolidine derivatives as cholinergic agents. US patent 5,073, 560. 1991 Dec 17Google Scholar
  62. 62.
    Sabb AL, Stein RP, Vogel RL, et al. WAY-131256 is an orally active, efficacious, and in-vivo functionally selective M1 agonist. Drug Develop Res 1997; 40: 185–92Google Scholar
  63. 63.
    Loudon JM, Bromidge SM, Brown F, et al. SB 202026: a novel muscarinic partial agonist with functional selectivity for M1 receptors. J Pharmacol Exp Ther 1997; 283: 1059–68PubMedGoogle Scholar
  64. 64.
    Kumar R, Orgogozo J. Efficacy and safety of SB 202026 as a symptomatic treatment for Alzheimer’s disease. In: Iqbal K, Winblad B, Nishimura T, et al., editors. Alzheimer’s disease: biology, diagnosis and therapeutics. New York (NY): John Wiley and Sons, 1997: 677–85Google Scholar
  65. 65.
    Ensinger HA, Bechtel WD, Birke FW, et al. WAL 2014 FU (Talsaclidine): a preferentially neuron activating muscarinic agonist for the treatment of Alzheimer’s disease. Drug Develop Res 1997; 40: 144–57Google Scholar
  66. 66.
    Adamus WS, Leonard JP, Troger W. Phase I clinical trials with WAL 2014, a new muscarinic agonist for the treatment of Alzheimer’s disease. Life Sci 1995; 56: 883–90PubMedGoogle Scholar
  67. 67.
    Fisher A, Brandeis R, Pittel Z, et al. (+/−)Cis-2-methyl-spiro (1,3-oxathiolane-5,3′) quinuclidine (AF102B): a new M1 agonist attenuates cognitive dysfunctions in AF64A-treated rats. Neurosci Lett 1989; 102: 325–31PubMedGoogle Scholar
  68. 68.
    Fisher A, Brandeis R, Karton Y, et al. Cis-2-methyl-spiro(1,3-oxathiolane-5,3′) quinuclidine an M1 selective cholinergic agonist attenuates cognitive dysfunctions in an animal model of Alzheimer’s disease. J Pharmacol Exp Ther 1991; 257: 392–403PubMedGoogle Scholar
  69. 69.
    Fisher A, Gurwitz D, Barak D, et al. Rigid analogs of acetylcholine can be M1-selective agonists: implications for a rational treatment strategy in Alzheimer’s disease. Biorg Med Chem Lett 1992; 2: 839–44Google Scholar
  70. 70.
    Fisher A, Karton Y, Heldman E, et al. Progress in medicinal chemistry of novel selective muscarinic agonists. Drug Des Discov 1993; 9: 221–35PubMedGoogle Scholar
  71. 71.
    Brandeis R, Sapir M, Hafif N, et al. AF150(S): a new functionally selective M1 agonist improves cognitive performance in rats. Pharmacol Biochem Behav 1995; 51: 667–74PubMedGoogle Scholar
  72. 72.
    Fisher A, Brandeis R, Chapman S. M1 muscarinic agonist treatment reverses cognitive and cholinergic impairments of apolipoprotein E-deficient mice. J Neurochem 1998; 70: 1991–7PubMedGoogle Scholar
  73. 73.
    Chapman S, Fisher A, Weinstock M, et al. The effects of the acetylcholinesterase inhibitor ENA713 and the M1 agonist AF150(S) on apolipoprotein E deficient mice. J Physiol (Paris) 1998; 92: 299–303Google Scholar
  74. 74.
    McKinney A, Anderson D, Vella-Rountree L. Different agonist-receptor active conformations for rat brain M1 and M2 muscarinic receptors that are separately coupled to two biochemical effector systems. Mol Pharmacol 1988; 35: 39–47Google Scholar
  75. 75.
    Ono S, Saito Y, Ohgane N, et al. Heterogeneity of muscarinic autoreceptors and heteroreceptors in the rat brain: effects of a novel M1 agonist, AF102B. Eur J Pharmacol 1989; 155: 77–84Google Scholar
  76. 76.
    Mochida S, Mizobe F, Fisher A, et al. Dual synaptic effects of activating M1-receptors, in superior cervical ganglia of rabbits. Brain Res 1988; 455(1): 9–17PubMedGoogle Scholar
  77. 77.
    Mattson MP, Barger SW, Cheng B, et al. β-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer’s disease. TINS 1993; 16: 409–14PubMedGoogle Scholar
  78. 78.
    Nitsch RM. Muscarinic receptors regulate amyloid precursor protein processing. In: Fisher A, editor. Muscarinic agonists and Alzheimer’s Disease. Austin (TX): RG Landes Company, Medical Intelligence Unit, 1996: 45–54Google Scholar
  79. 79.
    Muller DM, Mendia K, Farber SA. Muscarinic M1 receptor agonists increase the secretion of the amyloid precursor protein ectodomain. Life Sci 1997; 60: 985–91PubMedGoogle Scholar
  80. 80.
    Gray C, Hawkins J, Clark MSG, et al. SB 202026: a functionally M1 selective partial agonist alters processing of amyloid precursor protein at the cell surface [abstract]. Neurobiol Aging 1996; 17 Suppl.: 118Google Scholar
  81. 81.
    Pittel Z, Heldman E, Barg J, et al. Muscarinic control of amyloid precursor protein secretion in rat cerebral cortex and cerebellum. Brain Res 1996; 742: 299–304PubMedGoogle Scholar
  82. 82.
    Fisher A, Brandeis R, Haring R, et al. Novel M1 muscarinic agonists in treatment and delaying the progression of Alzheimer’s disease: a unifying hypothesis. J Physiol (Paris) 1998; 92: 337–40Google Scholar
  83. 83.
    Farber SA, Nitsch RM, Schulz JG, et al. Regulated secretion of β-amyloid precursor protein in rat brain. JNeurosci 1995; 15: 7442–51Google Scholar
  84. 84.
    Growdon JH. Muscarinic agonists in Alzheimer’s disease. Life Sci 1997; 60: 993–8PubMedGoogle Scholar
  85. 85.
    Lee VM-Y, Balin BJ, Otvos L, et al. A68: a major subunit of paired helical filaments and derivatized forms of normal tau. Science 1991; 251: 675–8PubMedGoogle Scholar
  86. 86.
    Gordon I, Grauer E, Genis I, et al. Memory deficits and cholinergic impairments in apolipoprotein E-deficient mice. Neurosci Lett 1995; 199: 1–4PubMedGoogle Scholar
  87. 87.
    Nakahara N, Iga Y, Mizobe F, et al. Amelioration of experimental amnesia (passive avoidance failure) in rodents by the selective M1 agonist AF102B. Jpn J Pharmacol 1988; 48: 502–6PubMedGoogle Scholar
  88. 88.
    Nakahara N, Iga Y, Saito Y, et al. Beneficial effects of FKS-508 (AF102B), a selective M1 muscarinic agonist, on the impaired working memory in AF64A-treated rats. Jpn J Pharmacol 1989; 51: 539–47PubMedGoogle Scholar
  89. 89.
    Brandeis R, Dachir S, Sapir M, et al. Reversal of age-related cognitive impairments by an M1 cholinergic agonist — AF102B. Pharmacol Biochem Behav 1990; 36: 89–95PubMedGoogle Scholar
  90. 90.
    O’Neil J, Fitten LJ, Siembieda D, et al. Effects of AF102B and tacrine on delayed match-to-sample in monkeys. Prog Neuropsychopharmacol Biol Psychiatry 1998; 22: 665–78Google Scholar
  91. 91.
    Vincent GP, Sepinwall J. AF102B, a novel M1 agonist, enhanced spatial learning in C57BL/10 mice with a long duration of action. Brain Res 1992; 597: 264–8PubMedGoogle Scholar
  92. 92.
    Roses AD. Apolipoprotein E affects the rate of Alzheimer disease expression: beta-amyloid burden is of secondary consequence dependent on APOE genotype and duration of disease. J Neuropathol Exp Neurol 1994; 53: 429–37PubMedGoogle Scholar
  93. 93.
    Poirier J, Delisle MC, Quirion R, et al. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci U S A 1995; 92(26): 12260–4PubMedGoogle Scholar
  94. 94.
    Davis KL, Hollander, E, Davidson M, et al. Induction of depression with oxotremorine in patients with Alzheimer’s disease. Am J Psychiatry 1987; 144: 468–71PubMedGoogle Scholar
  95. 95.
    Spiegel R. Cholinergic drugs, affective disorders and dementia: problems of clinical research. Acta Psychiatr Scand 1991; 366 Suppl.: 66–9Google Scholar
  96. 96.
    Penn RD, Martin EM, Wilson RS, et al. Intraventricular bethanechol infusion for Alzheimer’s disease. Neurology 1988; 38: 219–22PubMedGoogle Scholar
  97. 97.
    Soncrant TT, Raffaele KC, Asthana S, et al. Memory improvement without toxicity during chronic, low dose intravenous arecoline in Alzheimer’s disease. Psychopharmacol 1993; 112: 421–7Google Scholar
  98. 98.
    Sramek JJ, Cutler NR, Hurley DJ, et al. The utility of salivary amylase as an evaluation of M3 muscarinic agonist activity in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 1995; 19: 85–91PubMedGoogle Scholar
  99. 99.
    Farde L, Suhara T, Halldin C, et al. PET study of the M1-Agonists [11C]xanomeline and [11C]butylthio-TZTP in monkey and man. Dementia 1996; 7: 187–95PubMedGoogle Scholar
  100. 100.
    Delong AF, Bonate PL, Gillespie T, et al. Absorption distribution, metabolism and elimination of radiolabeled xanomeline in healthy male subjects. In: Hanin I, Yoshida M, Fisher A, editors. Alzheimer’s and Parkinson diseases: recent developments. New York (NY): Plenum Press, 1995: 463–8Google Scholar
  101. 101.
    Bodick NC, Offen WW, Levey AI, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol 1997; 54: 465–73PubMedGoogle Scholar
  102. 102.
    Lilly to develop Alzheimer’s patch. SCRIP 1996; 2144: 22 [online]. Available from: URL: [Accessed 1999 Jun 20]
  103. 103.
    Medina A, Bodick N, Goldberger AL, et al. Effects of central muscarinic-1 receptor stimulation on blood pressure regulation. Hypertension 1997; 29: 828–34PubMedGoogle Scholar
  104. 104.
    Marketletter. April 27, 1998; Alzheimer Research Forum [online]. Available from: URL: [Accessed 1999 Jun 20]
  105. 105.
    Hoover T, Breslin E, Bridging study in the clinical development of milameline (CI-979/RU 35926), a novel muscarinic agonist [abstract]. Neurobiol Aging 1996; Suppl. 17: S139Google Scholar
  106. 106.
    Alzheimer Research Forum [online]. Available from: URL: [Accessed 1999 Jun 20]Google Scholar
  107. 107.
    Davis RE, Doyle PD, Carroll RT, et al. Cholinergic therapies for Alzheimer’s disease. Palliative or disease altering? Arneimittelforschung 1995; 45: 425–31Google Scholar
  108. 108.
    Sramek JJ, Sedman AT, Reece PA, et al. Safety and tolerability of CI-979 in patients with Alzheimer’s disease. Life Sci 1995; 57: 503–10PubMedGoogle Scholar
  109. 109.
    Dethloff LA, Chang T, Courtney CL. Toxicological comparison of a muscarinic agonist given to rats by gavage or in the diet. Food Chem Toxicol 1996; 34: 407–22PubMedGoogle Scholar
  110. 110.
    Alzheimer’s disease — drug status update. ID Research Alerts 1997; 2 (8): 383-91Google Scholar
  111. 111.
    Sramek JJ, Hurley DJ, Wardle TS, et al. The safety and tolerance of xanomeline tartrate in patients with Alzheimer’s disease. J Clin Pharmacol 1995; 35: 800–6PubMedGoogle Scholar
  112. 112.
    Jope RS. Cholinergic muscarinic receptor signalling by phosphoinositides signal transduction system in Alzheimer’s disease. Alzheimer’s Dis Rev 1996; 1: 2–14Google Scholar
  113. 113.
    Yan GM, Lin SZ, Irwin RP, et al. Activation of muscarinic cholinergic receptors blocks apoptosis of cultured cerebellar granule neurons. Mol Pharmacol 1996; 47: 257Google Scholar
  114. 114.
    Hellweg R, von Richthofen S, Anders D, et al. The time course of nerve growth factor content in different neuropsychiatric disease — a unifying hypothesis. J Neural Transm 1988; 105: 871–903Google Scholar
  115. 115.
    Nordberg A, Amberla K, Shigeta M. Long term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities. Alzheimer Dis Assoc Disord 1998; 12: 228–37PubMedGoogle Scholar
  116. 116.
    Perry E, Court J, Goodchild R, et al. Clinical neurochemistry: developments in dementia research based on brain bank material. J Neural Transm 1998; 105: 915–33PubMedGoogle Scholar
  117. 117.
    Lander CJ, Celesia GG, Magnuson DJ, et al. Regional alterations in M1 muscarinic receptor-G protein coupling in Alzheimer’s disease. J Neuropath Exp Neurol 1995; 54: 783–9Google Scholar
  118. 118.
    Kelly JF, Furukawa K, Barger SW, et al. Amyloid β-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons. Proc Natl Acad Sci 1996; 96: 6753–8Google Scholar
  119. 119.
    Jope RS, Song L, Powers RE. Cholinergic activation of phosphoinositide signalling is impaired in Alzheimer’s disease brain. Neurobiol Aging 1997; 18: 111–20PubMedGoogle Scholar
  120. 120.
    Ferrari-DiLeo G, Mash DC, Flynn DD. Attenuation of muscarinic receptor-G-protein interaction in Alzheimer disease. Mol Chem Neuropathol 1995; 24: 69–91PubMedGoogle Scholar
  121. 121.
    Hoshi M, Takashima A, Murayama M, et al. Nontoxic amyloid β peptide 1–42 suppresses acetylcholine synthesis. J Biol Chem 1997; 272: 2038–41PubMedGoogle Scholar
  122. 122.
    Abe E, Casamenti F, Giovannelli L, et al. Administration of amyloid beta-peptides into the medial septum of rats decreases acetylcholine release from hippocampus in vivo. Brain Res 1994; 636: 162–4PubMedGoogle Scholar
  123. 123.
    Walter J, Grunberg J, Capell A, et al. Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C. Proc Natl Acad Sci U S A 1997; 94: 5349–54PubMedGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  1. 1.Israel Institute for Biological ResearchNess-ZionaIsrael

Personalised recommendations