Synthesis and modeling studies of a potent conformationally rigid muscarinic agonist: 1-azabicyclo[2.2.1]heptanespirofuranone [1]

Journal of Medicinal Chemistry

Volumn 41, Issue 22, 1998, Pages 4181-4185

  Wu, Edwin S C ^a,b   Kover, Alexander ^a,c   Semus, Simon F ^a,d  

^a Astra Arcus USA   (United States)

^b ScinoPharm   (Taiwan)

^c BRISTOL MYERS SQUIBB   (United States)

^d PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 AZABICYCLO[2.2.1]HEPTANE SPIROFURANONE; 3 (3 METHYL 1,2,4 OXADIAZOL 5 YL) 1 AZABICYCLO[2.2.1]HEPTANE; ACETYLCHOLINE; CARBACHOL; FURANONE DERIVATIVE; MUSCARINIC AGENT; OXOTREMORINE M; QUINUCLIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL TISSUE; BRAIN SLICE; CONTROLLED STUDY; DRUG CONFORMATION; DRUG DESIGN; DRUG POTENCY; DRUG SYNTHESIS; GUINEA PIG; HIPPOCAMPUS; LETTER; MOLECULAR MODEL; NONHUMAN; QUANTITATIVE STRUCTURE ACTIVITY RELATION; RAT; X RAY CRYSTALLOGRAPHY;

ANIMALS; BICYCLO COMPOUNDS, HETEROCYCLIC; CRYSTALLOGRAPHY, X-RAY; CYCLIC AMP; GUINEA PIGS; HIPPOCAMPUS; HYDROLYSIS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MUSCARINIC AGONISTS; MYOCARDIUM; PHOSPHATIDYLINOSITOLS; RATS; SPIRO COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0032561223     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980192x     Document Type: Letter

References (40)

1. (a) Sitaram, N. Cholinergic Hypothesis of Human Memory: Review of Basic and Clinical Studies. Drug Dev. Res. 1984, 4, 481-488.
2. (b) Bartuus, R. T.; Dean, R. L., III. The Cholinergic Hypothesis of Geriatric Memory Dysfunction. Science 1982, 217, 408-417.
3. (c) Palmer, A. M.; Gershon, S. Is the Neuronal Basis of Alzheimer's Disease Cholinergic or Glutamatergic? FASEB J. 1990, 4, 2745-2752.
4. (a) Hannon, H. E.; Bymaster, F. P.; Calligaro, D. O.; Greenwood, B.; Mitch, C. H.; Sawyer, B. D.; Ward, J. S.; Wong, D. T.; Olesen, P. H.; Sheardown, M. J.; Swedberg, D. B.; Suzdak, P. D.; Sauerberg, P. Xanomeline: A novel muscarinic receptor agonist with functional selectivity for M1 receptors. J. Pharmacol. Exp. Ther. 1994, 269, 271.
5. (b) Bryson, H. M.; Benfield, P. Donepezil. Drugs Aging 1997, 10, 234-241.
6. (c) Anand, R.; Gharabawi, G.; Enz, A. Efficacy and safety results of the early phase studies with Exelon(TM) (ENA-713) in Alzheimer's disease: An overview. J. Drug Dev. Clin. Pract. 1996, 21, 766-767.
7. Sramek, J. J.; Hurley, D. J.; Wardle, T. S.; Saatterwhite, J. H.; Hourani, J.; Dies, F.; Cutler, N. R. The safety and tolerance of xanomeline tartrate in patients with Alzheimer's disease. J. Clin. Pharmacol. 1995, 35, 800-806.
8. (a) Canepa, F. G.; Pauling, P.; Sorum, H. Structure of acetylcholine and other substrates of cholinergic systems. Nature 1963, 210, 907.
9. (b) Culvenor, C. C. J.; Ham, N. S. Structure of acetylcholine and other substrates of cholinergic systems. The proton magnetic resonance spectrum and conformation of acetylcholine. Chem. Commun. 1966, 537.
10. (c) Schulman, J. M.; Sabio, M. L.; Disch, R. L. Recognition of cholinergic agonists by the muscarinic receptor. 1. Acetylcholine and other agonists with the NCCOCC backbone. J. Med. Chem. 1983, 26, 817-823.
11. (d) Krogsgaard-Larsen, P.; Jensen, B.; Falch, E.; Jørgensen, F. S. Heterocyclic Muscarinic Agonists: Structural and Therapeutical Aspects. Drugs Future 1989, 15, 541-561.
12. (e) Schulman, J. M.; Disch, R. L. On the recognition of cholinergic agonists by the muscarinic receptor. Trends Pharmacol. Sci. 1986, 7, 263-264.
13. (f) Snyder, J. P. Molecular models for muscarinic receptors. Trends Pharmacol. Sci. 1985, 6, 464-465.
14. (a) Nordvall, G.; Hacksell, U. Binding-site modeling of the muscarinic m1 receptor: a combination of homology-based and indirect approaches. J. Med. Chem. 1993, 36, 967-976.
15. (b) Shapiro, G.; Floersheim, P.; Boelsterli, J.; Amstutz, R.; Bolliger, G.; Gammenthaler, H.; Gmelim, G.; Supavilai, P.; Walkinshaw, M. Muscarinic activity of the thiolactone, lactam, lactol, and thiolactol analogues of pilocarpine and a hypothetical model for the binding of agonists to the m1 receptor. J. Med. Chem. 1992, 35, 15-27.
16. (a) MacLeod, A. M.; Baker, R.; Herbert, R. H.; Lewis, R. T.; Madarde, M.; Street, L. J. Synthesis of azanorbornyl-spirodioxolanes related to the muscarinic agonist AF30. Tetrahedron Lett. 1992, 33, 4217-4220.
17. (b) Shapiro, G.; Floersheim, P.; Amstutz, R.; Boddeke, H.; Bolliger, G.; Cottens, S.; Enz, A.; Gmelin, G.; Gull, P.; Supavilai, P. Muscarinic agonist SAR of azaspirodioxolanes. Bioorg. Med. Chem. Lett. 1992, 2 (8), 815-820.
18. (c) Lewis, R. T.; MacLeod, A. M.; Street, L. J.; Kulagowski, J. J.; Baker, R. Abstracts of Papers; 203th National Meeting of the American Chemical Society, San Francisco, CA; American Chemical Society; Washington, DC, 1992; MEDI 102.
19. (d) Saunders, J.; Showell, G. A.; Baker, R.; Freedman, S. B.; Hill, D.; McKnight, A.; Newberry, N.; Salamome, J. D.; Hirshfield, J.; Springer, J. P. Synthesis and characterization of all four isomers of the muscarinic agonist 2′-methylspiro[1-azabicyclo[2.2.2]octane-3,4′[1,3]dioxolane]. J. Med. Chem. 1987, 30, 969-975.
20. (a) Wu, E. S. C.; Griffith, R.; Kover, A.; Loch, J. T., III; Mullen, G.; Murray, R. J.; Blosser, J. C.; Machulskis, A. C.; McCreedy, S. A. In Vitro Muscarinic Activity of Novel Spiromuscarones and Related Analogues. J. Med. Chem. 1995, 38, 1558-1570.
21. (b) Tsukamoto, S.; Fujii, M.; Yasunaga, T.; Matsuda, K.; Wanibuchi, F.; Hidaka, K.; Furuya, T.; Tamura, T. Synthesis and structure-activity studies of a series of 1-oxa-8-azaspiro[4.5]decanes as M1 muscarinic agonists. Bull. Chem. Pharm. 1995, 43, 842-52.
22. (c) Wu, E. S. C.; Mack, R. A.; Kover, A.; Loch, J. T., III; Mullen, G.; Murray, R. J.; Gordon, J.; Machulskis, A. C.; McCreedy, S. A.; Blosser, J. C. Synthesis and Biological Activity of Enantiomers of a Conformationally Restricted Muscarone Analogue. Bioorg. Med. Chem. Lett. 1995, 5, 1813-1818.
23. (a) Street, L. J.; Baker, R.; Book, T.; Kneen, C. O.; MacLeod, A. M.; Merchant, K. J.; Showell, G. A.; Saunders, J.; Herbert, R. H.; Freedman, S. B.; Harley, E. A. Synthesis and biological activity of 1,2,4-oxadiazole derivatives: highly potent and efficacious agonists for cortical muscarinic receptors. J. Med. Chem. 1990, 35, 2690-2697.
24. (b) Freedman, S. B.; Haley, E. A.; Patel, S.; Newberry, N. R.; Gilbert, M. J.; McKnight, A. T.; Tang, J. K.; Maguire, J. J.; Mudunkotuwa, N. T.; Baker, R.; Street, L. J.; MacLeod, A. M.; Saunders, J.; Iversen, L. L. A novel series of nonquaternary oxadiazoles acting as full agonists at muscarinic receptors. Br. J. Pharmacol. 1990, 101, 575-580.
25. The overall yield, starting from the ketone 2, of the fumarate salt of pure 1a (the syn isomer) which was isolated and purified from a mixture of syn and anti isomers of 1 was 6%.
26. (a) Tecle, H.; Lauffer, D. J.; Mirzadegan, T.; Moos, W. H.; Moorland, D. W.; Pavia, M. R.; Scharwz, R. D.; Davis, R. E. Synthesis and SAR of bulky 1-azabicyclo[2.2.1]-3-one oximes as muscarinic receptor subtype selective agonists. Life Sci. 1992, 52, 505.
27. (b) Tecle, H.; Lauffer, D. J.; Mirzadegan, T.; Moos, W. H.; Moorland, D. W.; Pavia, M. R.; Scharwz, R. D.; Davis, R. E. A rationale for the design and synthesis of m1 selective muscarinic agonists. Bioorg. Med. Chem. Lett. 1992, 2, 821.
28. (c) Moos, W. H.; Bergmeier, S. C.; Coughenour, L. L.; Davis, R. E.; Hershenson, F. M.; Kester, J. A.; McKee, J. S.; Marriott, J. G.; Scharwz, R. D.; Tecle, H.; Thomas, A. J. Cholinergic Agent: Effect of methyl substitution in a series of arecoline derivatives on building to muscarinic acetylcholine receptors. J. Pharm. Sci. 1992, 81, 1015-1019.
29. 12 (Figure 1), using the Sybyl suite of programs, version 6.3, Tripos Associates, St. Louis, MO. Geometry optimization was performed initially with the Tripos force field, followed by the 3-21G* Hamiltonian as implemented within Spartan, Wavefunction, Irvine, Ca. Atomic charges were calculated via natural population analysis and fitted to the electrostatic potential over the surface density. Potential energy isosurfaces were contoured to identify the maximal regions of electrostatic attraction and repulsion from the proton probe. The attractive areas were concentrated around the carbonyl and ring ether oxygens, along the vectors of their respective lone pairs. The molecular environment was subsequently sampled by an assortment of probe atoms and groups using GRID, Molecular Diversity Limited, Oxford, England, to identify potential interaction sites. Primary interaction domains were examined with carboxylic acid and aliphatic and aromatic hydroxyl probe groups. The resulting interaction maps obtained by GRID were consistent with the electrostatic potential maps and provided the pertinent information for construction of a pseudoreceptor site model.
30. 2 = 0.075.
31. Cramer, R. D., III; Patterson, D. E.; Bunce, J. E. Comparative Molecular Field Analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Med. Chem. 1988, 31, 5959-5967.
32. Wu, E. S. C.; Kover, A.; Loch, J. T., III; Rosenberg, L. P.; Semus, S. F.; Verhoest, P. R.; Gordon, J. C.; Machulskis, A. C.; McCreedy, S. A.; Zongrone, J.; Blosser, J. C. Acylhydrazones as M1/M3 selective muscarinic agonists. Bioorg. Med. Chem. Lett. 1996, 61, 2525-2530.
33. Kellogg, G. E.; Semus, S. F.; Abraham, D. J. HINT: a new method of empirical hydrophobic field calculation for CoMFA. J. Comput. Aided Mol. Des. 1991, 5, 545-552.
34. Fraser, C. M.; Wang, C.-D.; Robinson, D. A.; Gocayne, J.; Venter, J. C. Site-Directed Mutagenesis of m1 Muscarinic Acetylcholine Receptors: Conserved Aspartic Acids Play Importance Roles in Receptor Function. Mol. Pharmacol. 1989, 36, 840-847.
35. Wess, J.; Gdula, D.; Brann, M. R. Site-directed Mutagenesis of m3 Muscarinic Receptors: Identification of Threonine and Tyrosine Residues Involved in Agonist but not Antagonist Binding. EMDO J. 1991, 10, 3729-3734.
36. 7a
37. Carroll, P. J.; De Amici, M.; De Micheli, C.; Toma, L. Conformational Studies of Muscarone Analogues: X-ray Analysis and Molecular Mechanics Calculations. J. Med. Chem. 1992, 35, 305-309.
38. Chiou, C. Y.; Long, J. P.; Cannon, J. G.; Armstrong, P. D. The cholinergic effects and rates of hydrolysis of conformationally rigid analogues of acetylcholine. J. Pharmacol. Exp. Ther. 1969, 166, 243-248.
39. Waser, P. G. Chemistry and pharmacology of muscarinie, muscarone, and some related compounds. Pharmacol. Rev. 1961, 13, 465-515.
40. Casy, A. F. In Progress in Medicinal Chemistry; Ellis, G. P., West, G. B., Eds.; North-Holland Publishing: New York, 1975; Vol. 11, Chapter 1, pp 1-65.