10-Substituted 11-oxygenated (R)-aporphines: Synthesis, pharmacology, and modeling of 5-HT(1A) receptor interactions

Journal of Medicinal Chemistry

Volumn 39, Issue 18, 1996, Pages 3491-3502

  Hedberg, Martin H ^a   Jansen, Johanna M ^a   Nordvall, Gunnar ^b   Hjorth, Stephan ^c   Unelius, Lena ^b   Johansson, Anette M ^a  

^a UPPSALA UNIVERSITY   (Sweden)

^b R and D Laboratories   (Sweden)

^c UNIVERSITY OF GOTHENBURG   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

APORPHINE DERIVATIVE; DOPAMINE 1 RECEPTOR; DOPAMINE 2 RECEPTOR; SEROTONIN 1A AGONIST; SEROTONIN 1A RECEPTOR;

ARTICLE; BINDING AFFINITY; BINDING SITE; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; MOLECULAR MODEL; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION;

ANIMALS; HUMANS; MALE; MODELS, MOLECULAR; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, SEROTONIN; SEROTONIN AGONISTS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0029795725     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960188q     Document Type: Article

References (75)

1. (a) Neumeyer, J. L.; Baldessarini, R. J.; Arana, G. W.; Campbell, A. Aporphines as dopamine agonists and antagonists at central dopamine receptors. New Methods Drug Res. 1985, 1, 153-166.
2. (b) Gao, Y.; Ram, V. J.; Campbell, A.; Kula, N. S.; Baldessarini, R. J.; Neumeyer, J. L. Synthesis and structural requirements of N-substituted norapomorphines for affinity and activity at dopamine D-1, D-2, and agonist receptor sites in rat brain. J. Med. Chem. 1990, 33, 39-44.
3. (c) Schaus, J. M.; Titus, R. D.; Foreman, M. M.; Mason, N. R.; Truex, L. L. Aporphines as Antagonists of Dopamine D-1 Receptors. J. Med. Chem. 1990, 33, 600-607.
4. (d) Gao, Y.; Baldessarini, R. J.; Kula, N. S.; Neumeyer, J. L. Synthesis and Dopamine receptor affinities of enantiomers of 2-substituted apomorphines and their N-n-propyl analogues. J. Med. Chem. 1990, 33, 1800-1805.
5. (a) Cannon, J. G.; Mohan, P.; Bojarski, J.; Long, J. P.; Bhatnagar, R. K.; Leonard, P. A.; Flynn, J. R.; Chatterjee, T. K. (R)-(-)-10-Methyl-11-hydroxyaporphine: a highly selective serotonergic agonist. J. Med. Chem. 1988, 31, 313-318.
6. (b) Hedberg, M. H.; Johansson, A. M.; Hacksell, U. Facile syntheses of aporphine derivatives. J. Chem. Soc., Chem. Commun. 1992, 845-846.
7. 1A receptor interactions. J. Med. Chem. 1995, 38, 647-658.
8. (a) Saá, J. M.; Martorell, G.; García-Raso, A. Palladium-catalyzed cross-coupling reactions of highly hindered, electron-rich phenol triflates and organostannanes. J. Org. Chem. 1992, 57, 678-685.
9. (b) Echavarren, A. M.; Stille, J. K. Palladium-catalyzed coupling of aryl triflates with organostannanes. J. Am. Chem. Soc. 1987, 109, 5478-5486.
10. (c) Boong Kwon, H.; Mckee, B. H.; Stille, J. K. Palladium-catalyzed coupling reactions of (α-ethoxyvinyl)trimethylstannane with Vinyl and Aryl triflates. J. Org. Chem. 1990, 55, 3114-3118.
11. (d) Huth, A.; Beetz, I.; Schumann, I. Synthesis of diarylic compounds by palladium catalyzed reaction of aromatic triflates with boronic acids. Tetrahedron 1989, 45, 6679-6682.
12. (e) Fu, J.-m.; Snieckus, V. Connections to the ortho metalation strategy. Pd(0)-catalyzed cross-coupling of arylboronic acids with aryl triflates. Tetrahedron Lett. 1990, 31, 1665-1668.
13. Hedberg, M. H.; Johansson, A. M.; Fowler, C.; Terenius, L.; Hacksell, U. Palladium-catalyzed synthesis of C3-substituted 3-deoxymorphines. Bioorg. Med. Chem. Lett. 1994, 4, 2527-2532.
14. Tiffeneau, M. M. Action de l'anhydride acé sur les alcaloides de la série morphinique. (II) Etude des bases morphiniques chez lesquelles l'anhydride acétique ne détermine pas de rupture azotée. (Action of acetic anhydride upon alkaloids of the morphine series. II. Morphine bases in which acetic anhydride causes no rupture of the nitrogen linkage.) Bull. Soc. Chim. Fr. 1915, 17, 109-114.
15. Full experimental details for the synthesis of 7 are presented here.
16. Thompson, W. J.; Gaudino, J. A General synthesis of 5-arylnicotinates. J. Org. Chem. 1984, 49, 5237-5243.
17. Watanabe, T.; Miyaura, N.; Suzuki, A. Synthesis of sterically hindered biaryls via the palladium-catalyzed cross-coupling reaction of arylboronic acids or their esters with haloarenes. Synlett 1992, 207-210.
18. (a) Andersson, C.-M.; Hallberg, A. Regioselective palladium-catalyzed arylation of vinyl ethers with 4-nitrophenyl triflate. Control by addition of halide ion. J. Org. Chem. 1988, 53, 2112-2114.
19. (b) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S. α-Regioselectivity in palladium-catalyzed arylation of acyclic enol ethers. J. Org. Chem. 1992, 57, 1481-1486.
20. (a) Al-Ka'bi, J.; Farooqi, J. A.; Gore, P. H.; Moonga, B. S.; Waters, D. N. Kinetics of protiodeacylation of 4-substituted 2,6-dimethylbenzophenones in sulphuric acid. J. Chem. Res. Synop. 1989, 80-81.
21. (b) Keumi, T.; Morita, T.; Ozawa, Y.; Kitajima, H. The triflic acid-catalyzed deacylation and decarboxylation of polymethylbenzenecarbonyl derivatives under mild conditions. Bull. Chem. Soc. Jpn. 1989, 62, 599-601.
22. (a) von Braun, J.; Aust, E. Untersuchungen über Morphium-Alkaloide. V. (Morphine alkaloids. V.) Ber.-Dtsch. Chem. Ges. 1917, 50, 43-44.
23. (b) Smissman, E. E.; Makriyannis, A. C.; Walaszek, E. J. Synthesis and pharmacology of N-cyano-(β-arylethy)amines. J. Med. Chem. 1970, 13, 640-644.
24. (a) Olofson, R. A.; Martz, J. T.; Senet, J.-P. Piteau, M.; Malfroot, T. A new reagent for the selective, high-yield N-dealkylation of tertiary amines: improved syntheses of naltrexone and nalbuphine. J. Org. Chem. 1984, 49, 2081-2082.
25. (b) Gadamer, J.; Knoch, F. Ueber die Einwirkung von Chlorkohlensaurem Aethyl auf tertiäre, zyklische Amine (Alkaloide). (Action of ethyl chloroformate on tertiary cyclic amines (alkaloids).) Arch. Pharm. (Weinheim, Ger.) 1921, 259, 135-158.
26. Smissman, E. E.; Makriyannis, A. C. Azodicarboxylic acid esters as dealkylating agents. J. Org. Chem. 1973, 38, 1652-1657.
27. Cava, M. P.; Srinivasan, M. Conversion of aporphines into N-noraporphine alkaloids. J. Org. Chem. 1972, 37, 330-332.
28. Santamaria, J.; Ouchabane, R.; Rigaudy, J. Electron-transfer activation. Photochemical N-demethylation of tertiary amines. Tetrahedron Lett. 1989, 30, 2927-2928.
29. (a) von Braun, J.; Kruber, O.; Aust, E. Untersuchungen über Morphium-Alkaloide. I. Mitteilung. (Morphine alkaloids. I.) Ber.-Dtsch. Chem. Ges. 1914, 47, 2312-2330.
30. (b) Brine, G. A.; Boldt, K. G.; King Hart, C.; Carrol, F. I. The N-demethylation of morphine and codeine using methyl chloroformate. Org. Prep. Proc. Int. 1976, 8, 103-106.
31. (c) Abdel-Monem, M. M.; Portoghese, P. S. N-Demethylation of morphine and structurally related compounds with chloroformate esters. J. Med. Chem. 1972, 15, 208-210.
32. (d) Montzka, T. A.; Matiskella, J. D.; Partyka, R. A. 2,2,2-Trichloroethylehloroformate: a general reagent for demethylation of tertiary methylamines. Tetrahedron Lett. 1974, 14, 1325-1327.
33. (e) Olofson, R. A.; Schnur, R. C.; Bunes, L.; Pepe, J. P. Selective N-dealkylation of tertiary amines with vinyl chloroformate: an improved synthesis of naloxone. Tetrahedron Lett. 1977, 18, 1567-1570.
34. (f) Hosztafi, S.; Makleit, S.; Bognár, R. N-Demethylation of morphine alkaloids. Preparation of norneopine. Acta Chim. Acad. Sci. Hung. 1980, 103, 371-375.
35. 13C NMR study of N-formylmorphinanes and their 6,14-bridged derivatives; comparison with N-Me and N-H analogues. Magn. Reson. Chem. 1989, 27, 980-986.
36. Schellenberg, K. A. The synthesis of secondary and tertiary amines by borohydride reduction. J. Org. Chem. 1963, 28, 3259-3261.
37. Manoharan, T. S.; Madyastha, M.; Singh, B. B.; Bhatnagar, S. P.; Weiss, U. Convenient method for replacement of tertiary N-methyl by other alkyl groups: application to morphine alkaloids. Indian J. Chem. 1984, 23B, 5-11.
38. Rice, K. A rapid, high-yield conversion of codeine to morphine. J. Med. Chem. 1977, 20, 164-165.
39. Green, A. F.; Ruffell, G. K.; Walton, E. Morphine derivatives with antianalgesic action. J. Pharm. Pharmacol. 1954, 6, 390-397.
40. von Braun, J. Untersuchungen über Morphium-Alkaloide. III. Mitteilung. (Morphine alkaloids. III.) Ber.-Dtsch. Chem. Ges. 1916, 49, 977-989.
41. Clark, L. R.; Pessolano, A. A.; Weijlard, J.; Pfister, K., III. N-Substituted epoxymorphinanes. J. Am. Chem. Soc. 1953, 75, 4963-4967.
42. 2-receptor antagonists. J. Med. Chem. 1995, 38, 150-160.
43. (a) Allinger, N. L.; Yuh, Y. Quantum Chemistry Program Exchange 1980, 12, 395.
44. (b) Burkert, U.; Allinger, N. L. Molecular Mechanics; American Chemical Society: Washington, DC, 1982.
45. 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.
46. 3 receptors. Mol. Pharmacol. 1994, 46, 299-312.
47. 1A serotonin receptor. Mol. Pharmacol. 1993, 43, 516-520. The missing residue, located on the intracellular side of TM4, was added, and the sequence and numbering were corrected. Consequently, serine 198 (TM5) in refs 2c and 29 is numbered serine 199.
48. 1A receptor - a site-directed mutation study. FEBS Lett. 1992, 312, 259-262.
49. (a) Vedani, A.; Zbinden, P.; Snyder, J. P. Pseudo-receptor modeling: a new concept for the three-dimensional construction of receptor binding sites. J. Rec. Res. 1993, 13, 163-177.
50. (b) Snyder, J. P.; Rao, S. N.; Koehler, K. F.; Vedani, A. Minireceptors and pseudoreceptors. In 3D QSAR in drug design; Kubinyi, H., Ed.; Escom Science Publishers B.V.: Leiden, The Netherlands, 1993; pp 336-354.
51. (c) Vedani, A.; Zbinden, P.; Snyder, J. P.; Greenidge, P. A. Pseudoreceptor modeling: The construction of three-dimensional receptor surrogates. J. Am. Chem. Soc. 1995, 117, 4987-4994.
52. 1A receptors.
53. (a) Vedani, A.; Dunitz, J. D. Lone-pair directionality in hydrogen bond potential functions for molecular mechanics calculations: the inhibition of human carbonic anhydrase II by sulfonamides. J. Am. Chem. Soc. 1985, 107, 7653-7658.
54. (b) Vedani, A.; Huhta, D. W. A new force field for modeling metalloproteins. J. Am. Chem. Soc. 1990, 112, 4759-4767.
55. Baldessarini, R. J.; Kula, N. S.; Zong, R.; Neumeyer, J. L. Receptor affinities of aporphine enantiomers in rat brain tissue. Eur. J. Pharmacol. 1994, 254, 199-203.
56. (a) Andén, N.-E.; Carlsson, A.; Häggendal, J. Adrenergic mechanisms. Annu. Rev. Pharmacol. 1969, 9, 119-134.
57. (b) Aghajanian, G. K. Feedback regulation of central monoaminergic neurons: evidences from single cell recording studies. In Essays in neurochemistry and neuropharmacology; Youdim, M. B. H., Lovenberg, W., Sharman, D. F., Lagnado, J. R., Eds.; John Wiley and Sons: New York, 1978; pp 2-32.
58. (c) Hjorth, S.; Magnusson, T. The 5-HT1A agonist 8-OH-DPAT preferentially activates cell body 5-HT autoreceptors in rat brain in vivo. Naunyn-Schmiedeberg's Arch. Pharmacol. 1988, 338, 463-471.
59. (d) Neckers, L. M.; Neff, N. H.; Wyatt, R. J. Increased serotonin turnover in corpus striatum following an injection of kainic acid: evidence for neuronal feedback regulation of synthesis. Naunyn-Schmiedeberg's Arch. Pharmacol. 1979, 306, 173-177.
60. (a) Carlsson, A.; Lindqvist, M. Effect of ethanol on the hydroxylation of tyrosine and tryptophan in rat brain in vivo. J. Pharm. Pharmacol. 1973, 25, 437-440.
61. (b) Shum, A.; Sole, M. J.; van Loon, G. R. Simultaneous measurement of 5-hydroxytryptophan and L-dihydoxyphenylalanine by high-performance liquid chromatography with electrochemical detection. Measurement of serotonin and catecholamine turnover in discrete brain regions. J. Chromatogr. 1982, 228, 123-130.
62. (c) Hjorth, S.; Carlsson, A.; Lindberg, P.; Sanchez, D.; Wikström, H.; Arvidsson, L.-E.; Hacksell, U.; Nilsson, J. L. G. 8-Hydroxy-2-(dipropylamino)-tetralin, 8-OH-DPAT, a potent and selective ergot congener with central 5-HT-receptor stimulating activity. J. Neural Transm. 1982, 55, 169-188.
63. Carlsson, A.; Davis, J. N.; Kehr, W.; Lindqvist, M.; Atack, C. V. Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brain in vivo using an inhibitor of the aromatic amino acid decarboxylase. Naunyn-Schmiedeberg's Arch. Pharmacol. 1972, 275, 153-168.
64. 1A subtype. Eur. J. Pharmacol. 1985, 113. 463-464.
65. 3H-PAT. Nature 1983, 305, 140-142.
66. Arvidsson, L.-E.; Hacksell, U.; Nilsson, J. L. G.; Hjorth, S.; Carlsson, A.; Lindberg, P.; Sanchez, D.; Wikström, H. 8-Hydroxy-2-(dipropylamino)tetralin, a new centrally acting 5-hydrox-ytryptamine receptor agonist. J. Med. Chem. 1981, 24, 921-923.
67. Tricklebank, M.; Forler, C.; Fozard, J. R. The involvement of subtypes of the 5-HT1 receptor and of catecholaminergic systems in the behavioural response to 8-hydroxy-2-(di-n-propylamino)tetralin in the rat. Eur. J. Pharmacol. 1984, 106, 271-282.
68. Björk, L. Unpublished data.
69. (a) Joris, L.; von R. Schleyer, P. Intramolecular hydrogen bonding in aliphatic hydroxy ketones. J. Am. Chem. Soc. 1968, 90, 4599-4611.
70. (b) Pavia, D. L.; Lampman, G. M.; Kriz, G. S., Jr. Introduction to Spectroscopy, a Guide for Students of Organic Chemistry; Saunders College Publishing: Philadelphia, PA, 1979; p 49, ISBN 0-7216-7119-5 .
71. Cannon, J. G.; Raghupati, R.; Moe, S. T.; Johnson, A. K.; Long, J. P. Preparation and pharmacological evaluation of enantiomers of certain nonoxygenated aporphines: (+)- and (-)-aporphine (+)- and (-)-10-methylaporphine. J. Med. Chem. 1993, 36, 1316-1318.
72. Neville, G. A.; Ekiel, I.; Smith, I. C. P. High-resolution proton magnetic resonance spectra of morphine and its three O-acetyl derivatives. Magn. Reson. Chem. 1987, 25, 31-35.
73. McOmie, J. F. W.; Watts, M. L.; West, D. E. Demethylation of aryl methyl ethers by boron tribromide. Tetrahedron 1968, 24, 2289-2292.
74. Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. Semianalytical treatment of solvation for molecular mechanics and dynamics. J. Am. Chem. Soc. 1990, 112, 6127-6129.
75. 1A receptors: behavioural and in vivo brain microdialysis studies. Life Sci. 1990, 46, 955-963.