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Syntheses of 7-Substituted α-Cyperone Derivatives for Selective Sigma-1 Receptor over Cannabinoid-1 Receptor Binding Affinities
Syntheses of 7-Substituted α-Cyperone Derivatives for Selective Sigma-1 Receptor over Cannabinoid-1 Receptor Binding Affinities
Bulletin of the Korean Chemical Society. 2013. Nov, 34(11): 3499-3502
Copyright © 2013, Korea Chemical Society
  • Received : July 05, 2013
  • Accepted : August 28, 2013
  • Published : November 20, 2013
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About the Authors
Ju-Young Park
Young-Gyun Shin
Kee-Won Kim
Department of Pharmacology, Institute for Medical Sciences, ChonBuk National University, Jeonju 561-180, Korea
Young-Bae Kwon
Department of Laboratory Animal Medicine, College of Veterinary Medicine, Chonbuk National University, Jeonju 561-180, Korea
Sung-Hwa Yoon

Abstract
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Experimental
Instruments and Chemicals. Melting points were obtained on a Fisher-Johns melting point apparatus. 1 H and 13 C NMR spectra were obtained on a Varian Gemini NMR spectrometer at 400 and 100 MHz, respectively. 1 H chemical shifts were recorded relative to TMS (trimethylsilane, 0 ppm) and 13 C chemical shifts relative to CDCl 3 (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 NaBH 4 (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 Na 2 SO 4 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(3 H )-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 Na 2 SO 4 and concentrated in vacuo . The residue was purified with silica gel chromatography to afford the product as a colorless oil (37 mg, 40% yield). 1 H NMR (CDCl 3 ) δ 1.16 (s, 3H, 4aC-C H 3 ), 1.70 (s, 3H, 1C-C H 3 ), 3.27 (s, 3H, OC H 3 ), 3.87 (s, 2H, C H 2 OCH 3 ), 4.96 (s, 1H, C(CH 2 OCH 3 )=C H H), 5.03 (s, 1H, C(CH 2 OCH 3 )=CH H ); 13 C NMR (CDCl 3 ) 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(3 H )-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 Na 2 SO 4 and concentrated in vacuo . The residue was purified with silica gel chromatography to afford the title compound as colorless oil (20 mg, 39% yield). 1 H NMR (CDCl 3 ) δ 0.90-0.98 (t, 6H, J = 7.2 Hz, N(CH 2 C H 3 ) 2 ), 1.16 (s, 3H, 4aC-C H 3 ), 2.36-2.46 (q, 4 H, N(C H 2 CH 3 )2), 2.95 (s, 2H, C(=CH 2 )C H 2 N), 4.87 (s, 1H, C(=C H H)CH 2 N), 4.94 (s, 1H, C(=CH H )CH 2 N); 13 C NMR (CDCl 3 ) 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. 24 25 Each tube contained 40 μg membrane protein, TME buffer and 0.1 nM of [ 3 H] 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 CB 1 receptor were performed using methods published previously in detail. 26 27 In brief, Each tube contained 300 μg membrane protein, Tris-HCl buffer (50 mM, pH 8.0) and 5 nM of [ 3 H]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.
Acknowledgements
Acknowledgments. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant No. 2011-0009050), and was partially supported by the Post Brain Korea 21 program.
References
Witte S. , Loew D. , Gaus W. 2005 Phytother. Res. 19 183 -    DOI : 10.1002/ptr.1609
Fava M. , Alpert J. , Nierenberg A. A. , Mischoulon D. , Otto M. W. , Zajecka J. , Murck H. , Rosenbaum J. F. 2005 J. Clin. Psychopharmacol. 25 441 -    DOI : 10.1097/01.jcp.0000178416.60426.29
Thongsaard W. , Marsden C. A. , Morris P. , Prior M. , Shah Y. B. 2005 Psychopharmacology 180 752 -
Yu H. H. , Lee D. H. , Seo S. J. , You Y. O. 2007 Am. J. Chin. Med. 35 497 -    DOI : 10.1142/S0192415X07005016
Kumar R. P. , Rajesh K. , Yogender M. , Dharmesh S. , Karthiyagini T. 2010 International Journal of Research in Ayurveda & Pharmacy 1 536 -
Gupta M. B. , Palit T. K. , Singh N. , Bhargava K. P. 1971 Indian J. Med. Res. 59 76 -
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. 2011 Brain Res. Bull. 84 394 -    DOI : 10.1016/j.brainresbull.2011.01.008
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. 2010 J. Med. Food 13 564 -    DOI : 10.1089/jmf.2009.1252
Horan B. , Gardner E. L. , Dewey S. L. , Brodie J. D. , Ashby C. R. 2001 Eur. J. Pharmacol. 426 R1 -    DOI : 10.1016/f0024-2999(01)01229-8
Brammer M. K. , Gilmore D. L. , Matsumoto R. R. 2006 Eur. J. Pharmacol. 553 141 -    DOI : 10.1016/j.ejphar.2006.09.038
Hayashi T. , Su T. P. 2005 Life Sciences 77 1612 -    DOI : 10.1016/j.lfs.2005.05.009
Pacher P. , Batkai S. , Kunos G. 2006 Pharmacol. Rev. 58 389 -    DOI : 10.1124/pr.58.3.2
Padgett L. W. 2005 Life Sci. 77 1767 -    DOI : 10.1016/j.lfs.2005.05.020
Jeong M. S. 2006 Ph.D. Thesis
Zhabinskii V. N. , Minnaard A. J. , Wijnberg J. B. , de Groot A. 1996 J. Org. Chem. 61 4022 -    DOI : 10.1021/jo9602534
Barbetti P. , Chiappini I. , Fardella G. , Menghini A. 1985 Planta Med. 51 471 -    DOI : 10.1055/s-2007-969564
Yeo H. , Kim K. , Kim J. , Choi Y. 1998 Phytochemistry 27 1129 -
Bohlmann F. , Jakupovic J. , Lonitz M. 1977 Chemische Berichte 110 301 -    DOI : 10.1002/cber.19771100132
Ahmed A. A. , Jakupovic J. , Bohlmann F. , Regaila H. A. , Ahmed A. M. 1990 Phytochemistry 29 2211 -    DOI : 10.1016/0031-9422(90)83040-8
Barrett H. C. , Buechi G. 1967 J. Am. Chem. Soc. 89 5665 -    DOI : 10.1021/ja00998a029
Rodriguez Jean 1991 1991 477 -
Xiong Z. , Yang J. , Li Y. 1996 Tetrahedron-Asymmetry 7 2607 -    DOI : 10.1016/0957-4166(96)00335-7
Effenberger F. , Mueller W. , Keller R. , Wild W. , Ziegler T. 1990 J. Org. Chem. 55 3064 -    DOI : 10.1021/jo00297a022
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. 2012 Neurochem. Int. 61 913 -    DOI : 10.1016/j.neuint.2012.01.025
Yarim M. , Koksal M. , Schepmann D. , Wunsch B. 2011 Chem. Biol. Drug Des. 78 869 -    DOI : 10.1111/j.1747-0285.2011.01215.x
Wiley J. L. , Compton D. R. , Dai D. , Lainton J. A. , Phillips M. , Huffman J. W. , Martin B. R. 1998 J. Pharmacol. Exp. Ther. 285 995 -
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. 2005 J. Med. Chem. 48 1823 -    DOI : 10.1021/jm040843r