Xanomeline: G selective muscarinic agonist for the treatment of Alzheimer's disease

Drug Development Research

Volumn 40, Issue 2, 1997, Pages 158-170

  Bymaster, Frank P ^a   Whitesitt, Celia A ^a   Shannon, Harlan E ^a   Delapp, Neil ^a   Ward, John S ^a   Calligaro, David O ^a   Shipley, Lisa A ^a   Buelke Sam, Judith L ^a   Bodick, Neil C ^a   Farde, Lars ^b   Sheardown, Malcolm J ^c   Olesen, Preben H ^c   Hansen, Kristian T ^c   Suzdak, Peter D ^c   Swedberg, Michael D B ^c   Sauerberg, Per ^c   Mitch, Charles H ^a  

^a ELI LILLY AND COMPANY   (United States)

^b KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^c NOVO NORDISK A S   (Denmark)

Author keywords

Alzheimer's disease; Behavior; Cognition; Dementia; Muscarinic agonist; Xanomeline

Indexed keywords

AMYLOID PRECURSOR PROTEIN; MUSCARINIC AGENT; MUSCARINIC RECEPTOR; OXOTREMORINE; PHOSPHATIDYLINOSITIDE; PILOCARPINE; RECEPTOR SUBTYPE; XANOMELINE;

ACETYLCHOLINE BRAIN LEVEL; ALZHEIMER DISEASE; ANIMAL BEHAVIOR; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; BLADDER; BRADYCARDIA; CELL LINE; CONTROLLED STUDY; DELUSION; DRUG SAFETY; GUINEA PIG; HALLUCINATION; HEART ATRIUM; HUMAN; HYPOTHERMIA; IN VITRO STUDY; INTRAPERITONEAL DRUG ADMINISTRATION; LOCOMOTION; MOUSE; NONHUMAN; RABBIT; RAT; RECEPTOR AFFINITY; REVIEW; SALIVATION; VAS DEFERENS;

EID: 0030927142     PISSN: 02724391     EISSN: None     Source Type: Journal    
DOI: 10.1002/(SICI)1098-2299(199702)40:2<158::AID-DDR6>3.0.CO;2-K     Document Type: Review

References (72)

1. Ashall F, Goate AM (1994): Role of the β-amyloid precursor protein in Alzheimer's disease. Trends Biol Sci 19:42-46.
2. Bartus RT, Dean RL, Beer B, Lippa AS (1982): Cholinergic hypothesis of geriatric memory dysfunction: A critical review. Science 217:408-417.
3. Baumgold J, Dyer K, Falcone JF, Bymaster FP (1995): Comparison of second messenger responses to muscarinic receptor stimulation in M1-transfected A9 L cells. Cell Signal 7:39-43.
4. Bernard V, Normand E, Bloch B (1992): Phenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes. J Neurosci 12:3591-3600.
5. Bodick NC, DeLong AF, Bonate PL, Gillespie T, Henry DP, Satterwhite JH, Lucas RA, Heaton J, Carter GV (1994): Xanomeline, a specific M1 agonist: Early clinical studies. In Giacobini E, Becker R (eds): Alzheimer's Disease Therapeutic Strategies. Boston: Birkhauser, pp 234-238.
6. Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Rasmussen K, Hurley DJ, Paul SM (1997): The effects of xanomeline, an M1-selective muscarinic agonist, on cognitive and behavioral symptoms in Alzheimer's disease. Arch Neurol, in press.
7. Bymaster FP, Heath I, Hendrix JC, Shannon HE (1993): Comparative behavioral and neurochemical activities of cholinergic antagonists in rats. J Pharmacol Exp Ther 267:16-24.
8. Bymaster FP, Wong DT, Mitch CH, Ward JS, Calligaro DO, Schoepp DD, Shannon HE, Sheardown MJ, Diesen PH, Suzdak PD, Swedberg MDB, Sauerberg P (1994): Neurochemical effects of the M1 agonist xanomeline (LY246708/NNC11-0232). J Pharmacol Exp Ther 269:282-289.
9. Christie JE, Shering A, Ferguson J, Glen AIM (1981): Physostigmine and arecoline: Effects of intravenous infusions in Alzheimer's Presenile Dementia. Br J Psychiatry 138:46-50.
10. Conklin BR, Brann MR, Buckley NJ, Ma AL, Bonner TI, Axelrod J (1988): Stimulation of arachidonic acid release and inhibition of mitogenesis by cloned genes for muscarinic receptor subtypes stably expressed in A9 L cells. Proc Natl Acad Sci USA 85:8698-8702.
11. Cornpropst JD, Occolowitz JL, Gillespie TA, Shipley LA (1993): Metabolism of xanomeline, a candidate drug in the treatment of Alzheimer's disease, in rat and monkey. In International Society for the Study of Xenobiotics Proceedings, Fifth North American ISSX Meeting 4, p. 256.
12. 3 muscarinic receptors in rat parotid gland couple to two second messenger systems. Am J Physiol 261 (Cell Physiol 30):C1063-C1073.
13. Davies P, Maloney AJF (1976): Selective loss of central cholinergic neurons of the Alzheimer's type [letter]. Lancet 2:1403.
14. DeHaven-Hudkins DL, Lanyon LF, Ford-Rice FY, Ator MA (1994): s recognition sites in brain and peripheral tissues. Characterization and effects of cytochrome P450 inhibitors. Biochem Pharmcatol 47:1231-1239.
15. Eckols K, DeLapp N (1995): Muscarinic agonist stimulation of cyclic AMP accumulation in pertussis toxin-treated CHO-m4 cells. Soc Neurosci Abs 21:2040.
16. Eekols K, Bymaster FP, Mitch CH, Shannon HE, Ward JS, DeLapp NW (1995): The muscarinic M1 agonist xanomeline increases soluble amyloid precursor protein release from Chinese hamster ovary-m1 Cells. Life Sci 57:1183-1190.
17. Eltze M (1988): Muscarinic M1- and M2-receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens. Eur J Pharmacol 151:205-221.
18. Eltze M (1994): Pathways involved in muscarinic M1 and M2 receptor stimulation in rabbit vas deferens. Eur J Pharmacol 263:31-37.
19. 11C]-butylthio-TZTP in monkey and man. Dementia 7:187-195.
20. Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, DolanUreno J (1992): A controlled trial of Tacrine in Alzheimer's Disease. JAMA 268:2523-2529.
21. Flynn DD, Weinstein DA, Mash DC (1991): Loss of high-affinity agonist binding to M1 muscarinic receptors in Alzheimer's disease: Implications for the failure of cholinergic replacement therapies. Ann Neurol 29:256-262.
22. Flynn DD, Ferrari-DiLeo G, Mash DC, Levey AI (1995): Differential regulation of molecular subtypes of molecular receptors in Alzheimer's disease. J Neurochem 64:1888-1891.
23. Freedman SB, Harley EA, Iversen LL (1988): Relative affinities of drugs acting at cholinoreceptors in displacing agonist and antagonist radioligands: The NM S/OXO-M ratio as an index of efficacy at cortical muscarinic receptors. Br J Pharmaeol 93:437-445.
24. Gillespie TA, Bonate PL, Cornpropst JD, DeLong AF, and Shipley LA (1993): Electrospray MS and MS/MS for metabolite identification in various animal and human biotransformation studies. Presented at the Forty-first ASMS Conference on Mass Spectrometry, San Francisco, CA, June 1-5.
25. Gilley DW, Wilson RS, Bennet DA, Bernard BA, Fox JH (1991): Predictors of behavioral disturbance in Alzheimer's disease. J Geront: Psych Sci 46:362-371.
26. Glick SD, Greenstein S (1972): Differential effects of scopolamine and mecamylamine on passive avoidance behavior. Life Sci 11:169-179.
27. Goodman Y, Mattson MP (1994): Secreted forms ofβ-amyloid precursor protein protect hippocampal neurons against amyloid β-peptide-in-duced oxidative injury. Exp Neurol 128:1-12.
28. Hass C, Selkoe DJ (1993): Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide. Cell 75:1039-1042.
29. Hu G-Y, Hvalby O, Walaas SI, Albert KA, Skjeflo P, Andersen P, Greengard P (1987): Protein kinase C injection into hippocampal pyramidal cells elicits features of long term potentiation. Nature (Lond) 328:426-429.
30. Hu J, Wang S, El-Fakahany EE (1991): Effects of agonist efficacy on desensitization of phosphoinositide hydrolysis mediated by m1 and m3 muscarinic receptors expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther 257:938-944.
31. Huff RA, Abou-Donia MB (1994): cis-Methyldioxolane specifically recognizes the m2 muscarinic receptor. J Neurochem 62:388-391.
32. Hung AY, Haas C, Nitsch RM, Qui WQ, Citron M, Wurtman RJ, Growdon JH, Selkoe D (1993): Activation of protein kinase C inhibits cellular production of the amyloid β-protein. J Biol Chem 268:22959-22962.
33. Jones SVP, Heilman CJ, Brann MR (1991): Functional responses of cloned muscarinic receptors expressed in CHO cells. Mol Pharmacol 40:242-247.
34. Jones SVP, Levey AI, Weiner DM (1992): Muscarinic acetylcholine receptors. In Brann MR (ed): Molecular Biology of G-Protein-Coupled Receptors. Boston: Birkhauser, pp 170-197.
35. Jope RS, Ling S, Xiaohua L, Powers R (1994): Impaired phosphoinositide hydrolysis in Alzheimer's disease brain. Neurobiol Aging 15:221-226.
36. Kenakin T (1993): Pharmacologic Analysis of Drug-Receptor Interaction. 2nd Ed. New York: Raven Press.
37. Lee VM-Y, Balin BJ, Otvos L, Trojanopwski JQ (1991): A68: A major subunit of paired helical filaments and derivatized forms of normal tau. Science 251:675-678.
38. Levey AI (1993): Immunological localization of m1-m5 muscarinic acetylcholine receptors in peripheral tissues and brain. Life Sci 52:441-448.
39. Marchi M, Raiteri M (1985): On the presence in the cerebral cortex of muscarinic receptor subtypes which differ in neuronal localization, function and pharmacological properties. J Pharm Exp Ther 235:230-233.
40. Mash DC, Flynn DD, Potter LT (1985): Loss of M2 muscarinic receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation. Science 228:1115-1117.
41. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985): Amyloid plaque core protein in Alzheimer's disease and Down Syndrome. Proc Natl Acad Sci USA 82:4245-4249.
42. Mitch CH, Bymaster FP, Calligaro DO, Quimby SJ, Schoepp DD, Wong DT, Shannon HE (1994): Muscarinic antagonist activity of 3-(5-alkoxy-oxazol-2-yl)-1,2,5,6-tetrahydropyridines. BioMed Chem Lett 4:2205-2210.
43. Mohs RC, Cohen L (1988): Alzheimer's Disease Assessment Scale (ADAS). Psychopharmacol Bull 24:627-628.
44. Mortimer JA, Ebbitt B, Jun S-P, Finch MD (1992): Predictors of cognitive and functional progression in patients with probable Alzheimer's disease. Neurology 42:1689-1696.
45. Mouradian MM, Mohr E, Williams JA, and Chase TN (1988): No response to high-dose muscarinic therapy in Alzheimer's disease. Neurology 38:606-608.
46. Nitsch RM, Slack BE, Wurtman RJ, Growden JH (1992): Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258:304-307.
47. Noronha-Blob L, Lovve V, Patton A, Canning B, Costello D, Kinnier WJ (1989): Muscarinic receptors: relationships among phosphoinositide breakdown, adenylate cyclase inhibition, in vitro detrusor muscle contractions and in vivo cystometrogram studies in guinea pig bladder. J Pharmacol Exp Ther 249:843-851.
48. Nose T, Takemoto H (1974): Effect of oxotremorine on homovanillic acid concentration in the striatum of the rat. Eur J Pharmacol 25:51-55.
49. Olesen PH, Sauerberg P, Treppendahl S, Larsson O, Sheardown MJ, Suzdak P, Mitch CH, Ward JS, Bymaster FP, Shannon HE, Swedberg MDB (1996): 3-Alkylthio-1,2,5-thiadiazolyl-azabicycles. Structure-activity relationships for antinociception mediated by central muscarinic receptors. Eur J Med Chem 31:221-230.
50. Patel S, Freedman SB (1994): The muscarinic receptor agonist L-658,903 modulates the in vivo accumulation of inositol monophosphates in mouse brain. Eur J Pharmacol 267:329-334.
51. Patterson MB, Bolger JP (1994): Assessment of behavioral symptoms in Alzheimer's disease. Alzheimer Dis Assoc Disord 8(suppl 3):4-20.
52. Pearce BD, Potter LT (1991): Coupling of m1-Muscarinic receptors to C-protein in Alzheimer's disease. Alzheimer Dis Assoc Disord 5:163-172.
53. 1 receptors coupled to phosphoinositide turnover. Brain Res 693:118-123.
54. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson P, Perry RH (1978): Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. BMJ 2:1457-1459.
55. Pomara N, Stanley M, LeWitt PA, Galloway M, Singh R, Deptula D (1992): Increased CSF HVA response to arecoline challenge in Alzheimer's disease. J Neural Transm 90:53-65.
56. Pontzer NJ, Crews FT (1990): Desensitization of muscarinic stimulated hippocampal cell firing is related to phosphoinositide hydrolysis and inhibited by lithium. J Pharmacol Exp Ther 253:921-929.
57. Quimby SJ, Shannon HE, Bymaster FP, Sauerberg P, Olesen PH, Sheardown MJ, Suzdak PD, Mitch CH (1994): Synthesis and structure activity relationships of alkyl substituted analogues of the functional M1 selective muscarinic receptor agonist xanomeline. BioMed Chem Lett 4:2205-2210.
58. Raiteri M, Leardi R, Marchi M (1984): Heterogeneity of presynaptic muscarinic receptors regulating neurotransmitter release in the rat brain. J Phannacol Exp Ther 228:209-214.
59. Richards M, van Giersbergen PLM (1995): Human muscarinic receptors expressed in A9L and CHO cells: Activation by full and partial agonists. Br J Pharmacol 114:1241-1249.
60. 1 muscarinic acetylcholine receptor regulates t phosphorylation in transfected PC12 cells. J Neurochem 66:877-880.
61. Sauerberg P, Kindtler JW, Nielsen L (1991): Muscarinic cholinergic agonists and antagonists of the 3-(3-alkyl-1,2,4-oxadiazol-5-yl)1,2,5,6-tetrahydropyridine type. Synthesis and structure activity relationships. J Med Chem 34:687-692.
62. Sauerberg P, Olesen PH, Nielsen S, Treppendahl S, Sheardown MJ, Honore T, Mitch CH, Ward JS, Pike AJ, Bymaster FP, Sawyer BD, and Shannon HE (1992a): Novel functional M1 selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines. J Med Chem 35:2274-2283.
63. Sauerberg P, Olesen PH, Suzdak PD, Sheardown MJ, Mitch CH, Quimby SJ, Ward JS, Bymaster FP, Sawyer BD, Shannon HE (1992b): Synthesis and structure-activity relationships of heterocyclic analogues of the functional M1 selective muscarinic agonist hexyloxy-TZTP. BioMed Chem Lett 2:809-814.
64. Schwarz RD, Davis RE, Jaen JC, Spencer CJ, Tecle H, Thomas AJ (1993): Characterization of muscarinic agonists in recombinant cell lines. Life Sci 52:465-172.
65. Shannon HE, Bymaster FP, Calligaro DO, Greenwood B, Mitch CH, Sawyer BD, Ward, JS, Wong DT, Olesen PH, Sheardown MJ, Suzdak PD, Sauerberg P (1994): Xanomeline: A novel muscarinic receptor agonist with functional selectivity for M1 receptors. J Pharmacol Exp Ther 269:271-281.
66. Shannon HE, Sawyer BD, Bemis KC, Bymaster FP, Heath I, Mitch CH, Ward JS (1993): Muscarinic M1 receptor agonist actions of muscarinic receptor agonists in rabbit vas deferens. Eur J Pharmacol 232:47-57.
67. 14C-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-l-methyl- pyndine in R344 rats and rhesus monkeys. International Society for the Study of Xenobiotics Proceedings, Fourth North American ISSX Meeting 4, p. 186.
68. Shipley LA, Cornpropst JD, Brown TJ, Satterwhite JH, Gillespie TA, Lachno DR, Carter GV, Lucas RA (1993): Human Plasma Pharmacokinetics and Metabolism of Xanomeline, a Potential Therapy for Alzheimer's Disease. International Society for the Study of Xenobiotics Proceedings, Fifth North American ISSX Meeting 4, p. 58.
69. Sramek JJ, Hurley DJ, Wardle TS, Satterwhite JH, Hourani DO, Dies F, Cutler NR (1995): The safety and tolerance of xanomeline tartrate in patients with Alzhcimcr's disease. J Clin Pharmacol 35:800-806.
70. Ward JS, Merritt L, Klimkowski J, Lamb ML, Mitch CH, Bymaster FP, Sawyer B, Shannon HE, Olesen PH, Honoré T, Sheardown MJ, Sauerberg P (1992): Novel functional M1 selective muscarinic agonists. 2. Synthesis and structure-activity relationships of 3-pyrazinyl-1,2,5,6-tetrahydro-1-methylpyridines. Construction of a molecular model for the M1 pharmacophore. J Med Chem 35:4011-4019.
71. Ward JS, Merritt L, Calligaro DO, Bymaster FP, Shannon HE, Sawyer, BD, Mitch CH, Deeter JB, Peters SC, Sheardown MJ, Olesen PH, Swedberg MDB, Sauerberg P (1995): Functionally selective m1 muscarinic agonists. 3. Side chains and azacycles contributing to functional muscarinic selectivity among pyrazinylazacycles. J Med Chem 38:3469-3481.
72. Wilffert B, Davidesko D, Timmermans PBMWM, van Zwieten PA (1983): Differential role of M-1 and M-2 receptors in sympathetic ganglia of the pithed nonnotensive rat in alpha adrenoceptor-mediated vasoconstriction. J Pharmacol Exp Ther 226:855-860.