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Syntheses of 7-Substituted α-Cyperone Derivatives for Selective Sigma-1 Receptor over Cannabinoid-1 Receptor Binding Affinities

  • Park, Ju-Young (Department of Molecular Science and Technology, Ajou University) ;
  • Shin, Young-Gyun (Department of Molecular Science and Technology, Ajou University) ;
  • Kim, Kee-Won (Department of Pharmacology, Institute for Medical Sciences, ChonBuk National University) ;
  • Kwon, Young-Bae (Department of Laboratory Animal Medicine, College of Veterinary Medicine, Chonbuk National University) ;
  • Yoon, Sung-Hwa (Department of Molecular Science and Technology, Ajou University)
  • 투고 : 2013.07.05
  • 심사 : 2013.08.28
  • 발행 : 2013.11.20

초록

키워드

Experimental

Instruments and Chemicals. Melting points were obtained on a Fisher-Johns melting point apparatus. 1H and 13C NMR spectra were obtained on a Varian Gemini NMR spectrometer at 400 and 100 MHz, respectively. 1H chemical shifts were recorded relative to TMS (trimethylsilane, 0 ppm) and 13C chemical shifts relative to CDCl3 (77.0 ppm) and coupling constants J in Hz. Abbreviations for signal multiplicities are as follows: s (singlet), d (doublet), t (triplet) and m (multiplet). ESI-MS spectra were obtained by Shimadzu LCMS-2010EV.

(2R,4aS,7R)-1,4a-Dimethyl-7-(prop-1-en-2-yl)2,3,4,4a, 5,6,7,8-octahydronaphthalen-2-ol (2): Compound 2 was prepared by following the previously reported procedure,15 and obtained as a yellow oil (3.21 g, 56% yield). The spectral data of the product were consistent with the previously reported data.

(4aS,7R)-7-(3-Chloroprop-1-en-2-yl)-1,4a-dimethyl-4, 4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (3): To a solution of α-cyperone 1 (50 mg, 0.4 mmol) in ethnaol (10 mL) at −18 ℃ was added NaBH4 (50 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 1 h. After the reaction mixture was quenched with 1 N aqueous HCl solution at 0 ℃, the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with silica gel chromatography to afford the titled compound as a yellow oil (35 mg, 57% yield). The spectral data of the product were consistent with the previously reported data.20

(4aS,7R)-7-Isopropyl-1,4a-dimethyl-4,4a,5,6,7,8-hexahydronaphthalen- 2(3H)-one (4): Compound 4 was prepared by following the previously reported procedure,21 and obtained as a yellow oil (120 mg, 61% yield). The spectral data of the product were consistent with the previously reported data.

(4aS,7R)-7-(3-Methoxyprop-1-en-2-yl)-1,4a-dimethyl- 4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (5): A solution of (4aS,7R)-7-(3-chloroprop-1-en-2-yl)-1,4a-dimethyl- 4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one 3 (100 mg, 0.45 mmol) and TEA (45 mg, 0.45 mmol) in MeOH (10 mL) was refluxed for 12 h. After being cooled to room temperature, the mixture was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with silica gel chromatography to afford the product as a colorless oil (37 mg, 40% yield). 1H NMR (CDCl3) δ 1.16 (s, 3H, 4aC-CH3), 1.70 (s, 3H, 1C-CH3), 3.27 (s, 3H, OCH3), 3.87 (s, 2H, CH2OCH3), 4.96 (s, 1H, C(CH2OCH3)=CHH), 5.03 (s, 1H, C(CH2OCH3)=CHH); 13C NMR (CDCl3) δ 198.75, 161.60, 149.34, 128.66, 110.94, 74.92, 58.00, 42.00, 41.67, 37.47, 35.90, 33.85, 33.21, 27.29, 22.58, 11.05.

(4aS,7R)-7-(3-Hydroxyprop-1-en-2-yl)-1,4a-dimethyl- 4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (6): Compound 6 was prepared by following the previously reported procedure,21 and obtained as a colorless oil (60 mg, 82% yield). The spectral data of the product were consistent with the previously reported data.

2-((2R,4aS)-4a,8-Dimethyl-7-oxo-1,2,3,4,4a,5,6,7-octahydronaphthalen- 2-yl)acrylic acid (7): Compound 7 was prepared by following the previously reported procedure,21 and obtained as a colorless oil (45 mg, 51% yield). The spectral data of the product were consistent with the previously reported data.

(4aS,7R)-7-(3-(Diethylamino)prop-1-en-2-yl)-1,4a-dimethyl- 4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (8): To a solution of (4aS,7R)-7-(3-chloroprop-1-en-2-yl)-1,4adimethyl- 4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one 3 (40.0 mg, 0.41 mmol) and TEA (0.20 mL, 0.50 mmol) in dichloromethane (10 mL) was added diethylamine (0.30 mL, 0.61 mmol) and refluxed for 8 h. After being cooled to room temperature, the mixture was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with silica gel chromatography to afford the title compound as colorless oil (20 mg, 39% yield). 1H NMR (CDCl3) δ 0.90-0.98 (t, 6H, J = 7.2 Hz, N(CH2CH3)2), 1.16 (s, 3H, 4aC-CH3), 2.36-2.46 (q, 4 H, N(CH2CH3)2), 2.95 (s, 2H, C(=CH2)CH2N), 4.87 (s, 1H, C(=CHH)CH2N), 4.94 (s, 1H, C(=CHH)CH2N); 13C NMR (CDCl3) δ 198.85, 162.37, 151.51, 128.38, 110.57, 58.53, 46.63, 42.07, 41.85, 37.42, 35.97, 33.84, 33.53, 27.26, 22.55, 11.79, 11.02; ESIMS: m/z 290.35 (M + H)+, 331.40 (M + ACN + H)+.

CB1 Receptor Binding Assay. Preparation of rat cerebral cortex membrane and binding assays for the sigma-1 receptor were performed using methods published previously in detail.2425 Each tube contained 40 μg membrane protein, TME buffer and 0.1 nM of [3H] CP-55,940 was incubated in total reaction volume of 500 μL for 60 min at 30 ℃. Nonspecific binding was determined in the presence of 10 μM CP-55,940. The incubation was terminated by rapid filtration through the presoaked filtermats by using the cell harvester. After being washed three times with the ice-cold Tris-HCl buffer, the filter was transferred to a liquid scintillation vial. After addition of EtOH and counting cocktail, the quantity of radioactivity was determined by liquid scintillation spectrometry.

Sigma-1 Receptor Binding Assay. Preparation of rat cortex membrane and binding assays for the CB1 receptor were performed using methods published previously in detail.2627 In brief, Each tube contained 300 μg membrane protein, Tris-HCl buffer (50 mM, pH 8.0) and 5 nM of [3H]pentazocine was incubated in total reaction volume of 500 μL for 60 min at 25 ℃. The incubation was terminated by rapid filtration through the presoaked filtermats by using the cell harvester. After being washed three times with the ice-cold Tris-HCl buffer, the filter was transferred to a liquid scintillation vial. After addition of EtOH and counting cocktail, the quantity of radioactivity was determined by liquid scintillation spectrometry.

참고문헌

  1. Witte, S.; Loew, D.; Gaus, W. Phytother. Res. 2005, 19, 183. https://doi.org/10.1002/ptr.1609
  2. Fava, M.; Alpert, J.; Nierenberg, A. A.; Mischoulon, D.; Otto, M. W.; Zajecka, J.; Murck, H.; Rosenbaum, J. F. J. Clin. Psychopharmacol. 2005, 25, 441. https://doi.org/10.1097/01.jcp.0000178416.60426.29
  3. Thongsaard, W.; Marsden, C. A.; Morris, P.; Prior, M.; Shah, Y. B. Psychopharmacology 2005, 180, 752.
  4. Yu, H. H.; Lee, D. H.; Seo, S. J.; You, Y. O. Am. J. Chin. Med. 2007, 35, 497. https://doi.org/10.1142/S0192415X07005016
  5. Kumar, R. P.; Rajesh, K.; Yogender, M.; Dharmesh, S.; Karthiyagini, T. International Journal of Research in Ayurveda & Pharmacy 2010, 1, 536.
  6. Gupta, M. B.; Palit, T. K.; Singh, N.; Bhargava, K. P. Indian J. Med. Res. 1971, 59, 76.
  7. Sunil, A. G.; Kesavanarayanan, K. S.; Kalaivani, P.; Sathiya, S.; Ranju, V.; Priya, R. J.; Pramila, B.; Paul, F. D.; Venkhatesh, J.; Babu, C. S. Brain Res. Bull. 2011, 84, 394. https://doi.org/10.1016/j.brainresbull.2011.01.008
  8. Lee, C. H.; Hwang, D. S.; Kim, H. G.; Oh, H.; Park, H.; Cho, J. H.; Lee, J. M.; Jang, J. B.; Lee, K. S.; Oh, M. S. J. Med. Food 2010, 13, 564. https://doi.org/10.1089/jmf.2009.1252
  9. Horan, B.; Gardner, E. L.; Dewey, S. L.; Brodie, J. D.; Ashby, C. R., Jr. Eur. J. Pharmacol. 2001, 426, R1. https://doi.org/10.1016/S0014-2999(01)01229-8
  10. Brammer, M. K.; Gilmore, D. L.; Matsumoto, R. R. Eur. J. Pharmacol. 2006, 553, 141. https://doi.org/10.1016/j.ejphar.2006.09.038
  11. Hayashi, T.; Su, T. P. Life Sciences 2005, 77, 1612. https://doi.org/10.1016/j.lfs.2005.05.009
  12. Pacher, P.; Batkai, S.; Kunos, G. Pharmacol. Rev. 2006, 58, 389. https://doi.org/10.1124/pr.58.3.2
  13. Padgett, L. W. Life Sci. 2005, 77, 1767. https://doi.org/10.1016/j.lfs.2005.05.020
  14. Jeong, M. S. Ph.D. Thesis Chonbuk National University, February 2006.
  15. Zhabinskii, V. N.; Minnaard, A. J.; Wijnberg, J. B.; de Groot, A. J. Org. Chem. 1996, 61, 4022. https://doi.org/10.1021/jo9602534
  16. Barbetti, P.; Chiappini, I.; Fardella, G.; Menghini, A. Planta Med. 1985, 51, 471. https://doi.org/10.1055/s-2007-969564
  17. Yeo, H.; Kim, K.; Kim, J.; Choi, Y. Phytochemistry 1998, 27, 1129.
  18. Bohlmann, F.; Jakupovic, J.; Lonitz, M. Chemische Berichte 1977, 110, 301. https://doi.org/10.1002/cber.19771100132
  19. Ahmed, A. A.; Jakupovic, J.; Bohlmann, F.; Regaila, H. A.; Ahmed, A. M. Phytochemistry 1990, 29, 2211. https://doi.org/10.1016/0031-9422(90)83040-8
  20. Barrett, H. C.; Buechi, G. J. Am. Chem. Soc. 1967, 89, 5665. https://doi.org/10.1021/ja00998a029
  21. Jean Rodriguez, J.-P. D. 1991, 1991, 477.
  22. Xiong, Z.; Yang, J.; Li, Y. Tetrahedron-Asymmetry 1996, 7, 2607. https://doi.org/10.1016/0957-4166(96)00335-7
  23. Effenberger, F.; Mueller, W.; Keller, R.; Wild, W.; Ziegler, T. J. Org. Chem. 1990, 55, 3064. https://doi.org/10.1021/jo00297a022
  24. Nam, Y.; Shin, E. J.; Yang, B. K.; Bach, J. H.; Jeong, J. H.; Chung, Y. H.; Park, E. S.; Li, Z.; Kim, K. W.; Kwon, Y. B.; Nabeshima, T.; Kim, H. C. Neurochem. Int. 2012, 61, 913. https://doi.org/10.1016/j.neuint.2012.01.025
  25. Yarim, M.; Koksal, M.; Schepmann, D.; Wunsch, B. Chem. Biol. Drug Des. 2011, 78, 869. https://doi.org/10.1111/j.1747-0285.2011.01215.x
  26. Wiley, J. L.; Compton, D. R.; Dai, D.; Lainton, J. A.; Phillips, M.; Huffman, J. W.; Martin, B. R. J. Pharmacol. Exp. Ther. 1998, 285, 995.
  27. Lange, J. H.; van Stuivenberg, H. H.; Coolen, H. K.; Adolfs, T. J.; McCreary, A. C.; Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J.; de Looff, W.; Verveer, P. C.; Kruse, C. G. J. Med. Chem. 2005, 48, 1823. https://doi.org/10.1021/jm040843r