New M1 Agonists: Selective Signaling, Neurotrophic-Like and Cognitive Effects — Implications in the Treatment of Alzheimer’s Disease

  • Abraham Fisher
  • Eliahu Heldman
  • David Gurwitz
  • Rachel Haring
  • Haim Meshulam
  • Rachel Brandeis
  • Zipora Pittel
  • Daniele Marciano
  • Michal Sapir
  • Dov Barak
  • Zvi Vogel
  • Yishai Karton
Part of the Advances in Behavioral Biology book series (ABBI, volume 44)

Abstract

To date five structurally different human muscarinic acetylcholine receptor (mAChR) subtypes (ml-m5) proteins have been cloned and expressed in suitable cell systems (Bonner et al., 1987). It is likely that the ml, m2, m3, and m4 AChRs fit the pharmacological definition of the M1, M2, M3 and M4 AChRs, respectively (Buckley et al., 1989; reviewed by Hulme et al., 1990). Muscarinic receptors are members of the G-protein coupled receptor superfamily. The mAChRs have two binding domains, a ligand-binding extracellular (and including membrane-spanning) domain and a G-protein binding intracellular domain. This second domain, by interaction with various G-proteins, controls and modulates second messenger systems. It was shown that the ml, m3 and m5 AChRs are closely related in sequence and apparently are functionally almost similar. When expressed in mammalian cells, these receptor subtypes couple efficiently to phosphoinositide (PI) turnover. The m2 and m4 AChRs are less related to the ml, m3 and m5 AChRs, and when expressed in mammalian cells are efficiently coupled to the inhibition of adenylate cyclase (Bonner et al., 1987; Hulme et al., 1990).

Keywords

Nerve Growth Factor Muscarinic Receptor Muscarinic Agonist Muscarinic Receptor Subtype mAChR 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.

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References

  1. Bartus, R.T., 1989, Drugs to treat age-related neurodegenerative problems. The final frontier of medical science? J. Am. Ger. Soc. 8: 680–695.Google Scholar
  2. Bonner, T.I., Buckley, N.J., Young, A.C., and Brann, M.R., 1987, Identification of a family of muscarinic acetylcholine receptor genes, Science 237: 527–532.PubMedCrossRefGoogle Scholar
  3. Buckley, A.N.J., Bonner, T.I., Buckley, C.M., and Brann, M., 1989, Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells, Mol. Pharmacol. 35: 469–476.PubMedGoogle Scholar
  4. Brandeis, R., Dachir, S., Sapir, M., Levy, A., and Fisher, A., 1990, Reversal of age-related cognitive impairments by an M1 cholinergic agonist–AF102B, Pharmacol. Biochem. Behay. 36, 89–95.CrossRefGoogle Scholar
  5. Bruel, A., Chergui, G., Columelli, S., Margelin, D., Roudier, M., Sinet, P.M., Prieur, M., Perignon, J.L., and Delabar, J., 1991, Reduced protein kinase C activity in sporadic Alzheimer’s disease fibroblasts, Neurosci. Lett. 133: 89–92.PubMedCrossRefGoogle Scholar
  6. Buxbaum, J.D., Oishi, M., Chen, H.I., Pinkas-Kramarski, R., Jaffe, E.A., Gandy, S.E., and Greengard, P., 1992, Cholinergic agonists and interleukin 1 regulate processing and secretion of Alzheimer ß/A4 amyloid protein precursor, Proc. Natl. Acad. Sci. USA. 89: 10075–10078.PubMedCrossRefGoogle Scholar
  7. Fisher, A, Brandeis, R., Pittel, Z, Karton, I., Sapir, M., Dachir, S., Levy, A., and Heldman, E., 1989, Cis-2-methyl-spiro(1,3-oxathiolane-5,3’)quinuclidine (AF102B): a new MI agonist attenuates cognitive dysfunctions in AF64A-treated rats, Neurosci. Lett. 102: 325–331.PubMedCrossRefGoogle Scholar
  8. Fisher, A., Brandeis, R., Karton, I., Pittel, Z., Gurwitz, D., Haring, R., Sapir, M., Levy, A., and Heldman, E., 1991a, Cis-2-methyl-spiro(1,3-oxathiolane-5,3’) quinuclidine an M1 selective cholinergie agonist attenuates cognitive dysfunctions in an animal model of Alzheimer’s disease, J. Pharmacol. Exp. Ther. 257: 392–403.PubMedGoogle Scholar
  9. Fisher, A., Segall Y., Shirin E., Karton Y., and H. Meshulam, H., 1991b, Spiro-nitrogen-bridged and unbridged heterocyclic compounds, US Patent Application (CIP), April; Priority: April 10, 1990.Google Scholar
  10. Fisher, A., Segall, Y., Meshulam, H., Shirin, E., Gurwitz, D., Haring, R., Brandeis, R., Segal, M., Markram, H., Pittel, Z., Fraser, C.M., Heldman, E., and Karton, Y., 1991c, AF150 and AF151: novel efficacious M1 muscarinic agonists. Soc. Neurosci. Abstr. 17, 388.Google Scholar
  11. Fisher, A., and Heldman, E., 1991, Cis-2-methyl-spiro(1,3-oxathiolane-5,3’)quinuclidine (AF102B) a new M1 agonist as a rational treatment strategy in Alzheimer’s disease - an overview. In: Basic, Clinical and Therapeutical Aspects of Alzheimer’s and Parkinson’s Diseases, Nagatsu, T., Fisher, A. and Yoshida, M., eds., New York and London, Plenum Press 35B: 309–319.Google Scholar
  12. Fisher, A., Gurwitz, D., Barak, D., Haring, R., Karton, Y., Brandeis, R., Pittel, Z., Marciano, D., Meshulam, H., Vogel, Z., and Heldman, E., 1992, Rigid analogs of acetylcholine can be M1-selective agonists: implications for a rational treatment strategy in Alzheimer’s disease, Bioorg. Med. Chem. Lett. 2: 839–844.CrossRefGoogle Scholar
  13. Fisher.A., Karton, Y., Heldman, E., Gurwitz, D., Haring, R., Meshulam, H., Brandeis, R., Pittel, Z., Segall, Y., Marciano, D., Markovitch, I., Samocha, Z., Shirin, E., Sapir, M., Green, B., Shoham, G., and Barak, D., 1993, Progress in medicinal chemistry of novel selective muscarinic agonists, Drug Design and Discovery 9: 221–235.Google Scholar
  14. Fisher A., Heldman, E., Gurwitz, D., Brandeis, R., Treves, T.A., Karton, Y. Verchovsky, R., Klimowsky, S., Meshulam, H., Pittel, Z., Marciano, D., and Korczyn A.D., 1994, Selective signaling via novel muscarinic agonists: implications for Alzheimer’s disease treatments and clinical update, Third Springfield International Symposium on Alzheimer Disease. Springfield, IL, USA, May 11–15.Google Scholar
  15. Fowler, C.J., O’Neill C., Garlind A., and Cowburn, R. F., 1990, Alzheimer’s disease: is there a problem beyond recognition, TIPS 11: 183–184.Google Scholar
  16. Giacobini, E. The cholinergic system in Alzheimer disease, 1990, in: Progress in Brain Research, S.M. Aquilonius and P.G. Gillberg, eds., Elsevier, Amsterdam 84: 321–332.Google Scholar
  17. Grammas, P., Roher, A.E., and Ball, M.L., 1994, Increased accumulation of cAMP in cerebral microvessels in Alzheimer’s Disease, Neurobiol. Aging 15: 113–116.PubMedCrossRefGoogle Scholar
  18. Gurwitz, D., Haring, R., Pinkas-Kramarski, R., Stein, R., and Fisher, A., 1993, Neurotrophic-like effects of AF102B, an M 1-selective muscarinic agonist, in PC12 cells transfected with M1 muscarinic receptors, Soc. Neurosci. Abstr. 19: 1767.Google Scholar
  19. Gurwitz, D., Haring, R, Heldman, E., Fraser, C. M., Manor, D., and Fisher, A., 1994, Discrete activation of transduction pathways associated with acetylcholine ml receptor by several muscarinic ligands, Eur. J. Pharmacol. 267: 21–31.PubMedCrossRefGoogle Scholar
  20. Harrison, P.J., Barton, A.J.L., McDonald, B., and Pearson, R.C.A., 1991a, Alzheimer’s disease: specific increases in a G-protein subunit (Gsa) mRNA in hippocampal and cortical neurons, Mol. Brain Res. 10: 71–81.PubMedCrossRefGoogle Scholar
  21. Harrison, P.J., Barton, A.J.L., Najlerahim, A., McDonald, B., and Pearson, R.C.A, 1991b,. Increased muscarinic receptor messenger RNA in Alzheimer’s disease temporal cortex demonstrated by in situ hybridization histochemistry, Brain Res. 9: 15–21.Google Scholar
  22. Hulme, E. C., Birdsall, N.J.M., and Buckley, N.J., 1990, Muscarinic receptor subtypes, Annu. Rev. Pharmacol. Toxicol. 30: 633–673.PubMedCrossRefGoogle Scholar
  23. Mochida S., Mizobe F., Fisher A., Kawanishi G., and Kobayashi H., 1988, Dual synaptic effects of activating M1-muscarinic receptors, in superior cervical ganglia of rabbits, Brain Res. 455: 9–17.PubMedCrossRefGoogle Scholar
  24. Nakahara, N., Iga, Y., Saito, Y., Mizobe, F., and Kawanishi, G., 1989, Beneficial effects of FKS-508 (AF102B), a selective ml muscarinic agonist, on the impaired working memory in AF64A-treated rats, Jpn. J. Pharmacol. 51: 539–547.PubMedCrossRefGoogle Scholar
  25. Nitsch R.N., Slack, B.E., Wurtman, R.J., and Growdon, J.H., 1992, Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors, Science 258: 304–307.PubMedCrossRefGoogle Scholar
  26. Ono, S., Saito, Y., Ohgane, N., Kawanishi, G., and Mizobe, F., 1989, Heterogeneity of muscarinic autoreceptors and heteroreceptors in the rat brain: effects of a novel M1 agonist, AF102B. Eur. J. Pharmacol. 155: 77–84.CrossRefGoogle Scholar
  27. Pinkas-Kramarski, R., Stein, R., Lindenboim, L., and Sokolovsky, M., 1992, Growth factor-like effects mediated by muscarinic receptors in PC12 M1 cells, J. Neurochem. 59: 2158–2166.PubMedCrossRefGoogle Scholar
  28. Potter, L.T., 1987, Muscarine receptors in the cortex and hippocampus in relation to the treatment of Alzheimer’s diseACe, in: International Symposium on Muscarinic Cholinergic Mechanisms. S. Cohen, and M. Sokolovsky, eds., Freund Publishing Ltd., London, pp. 294–301.Google Scholar
  29. Potter, L.T., 1992, Strategies for the treatment of Alzheimer’s disease: cholinergic agonists, in: Alzheimer’s Disease: New Treatment Strategies, Z.S. Khachaturian and J.P. Blass, eds., New York, Marcel Dekker, pp, 57–66.Google Scholar
  30. Segal, M., and Fisher, A., 1992, AF102B, an M1 muscarinic agonist, mimics some effects of acetylcholine on neurons of rat hippocampus slices, Eur. J. Pharmacol. 220: 103–106.PubMedCrossRefGoogle Scholar
  31. Svensson, A.L., Alafuzoff, I. and Nordberg, A., 1992, Characterization of muscarinic receptor subtypes in Alzheimer and control brain cortices by selective muscarinic antagonists, Brain Res. 596: 142–148.PubMedCrossRefGoogle Scholar
  32. Sugita, S., Uchimura, N., Jiang, Z.-G., and North, R.A., 1991, Distinct muscarinic receptors inhibit release of gama-aminobutyric acid and excitatory amino acids in mammalian brain, Proc. Natl. Acad. Sci. USA 88:2608–2611.Google Scholar
  33. Young, L.T., Warsh, J.J., Li, P.P., Siu, K.P., Becker, L., Gilbert, J., Homykiewicz, O., and Kish, S.J., 1991, Maturational and aging effects on guanine nucleotide binding protein immunoreactivity in human brain, Dey. Brain Res. 61: 243–248.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Abraham Fisher
    • 1
  • Eliahu Heldman
    • 1
  • David Gurwitz
    • 1
  • Rachel Haring
    • 1
  • Haim Meshulam
    • 1
  • Rachel Brandeis
    • 1
  • Zipora Pittel
    • 1
  • Daniele Marciano
    • 1
  • Michal Sapir
    • 1
  • Dov Barak
    • 1
  • Zvi Vogel
    • 2
  • Yishai Karton
    • 1
  1. 1.Israel Institute for Biological ResearchNess-ZionaIsrael
  2. 2.The Weizmann InstituteRehovotIsrael

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