YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Antinociceptive, Antiinflammtory and Antihypercholesterolemic Effects of Androstane and Cholestane Derivatives

Androstane과 Cholestane 유도체의 진통, 소염 및 항고지혈 효과

  • Kim, Hak-Soon (College of Pharmacy, Catholic University of Daegu) ;
  • Ma, Eun-Sook (College of Pharmacy, Catholic University of Daegu)
  • 김학순 (대구가톨릭대학교 약학대학) ;
  • 마은숙 (대구가톨릭대학교 약학대학)
  • Published : 2007.12.31
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Abstract

Seven epoxy- and hydroxyandrostane derivatives ($DH-1{\sim}DH-7$) and nine epoxy- and hydroxycholestane derivatives ($CH-1{\sim}CH-9$) with unsaturation in ring A and ring B were synthesized from DHEA and cholesterol, respectively. The antinociceptive effects of all synthesized compounds were measured by hot plate method. Most of androstane derivatives except $1{\alpha},2{\alpha}$-epoxy-4,6-androstadiene-3,17-dione (DH-3), and CH-6, CH-7 and CH-9 exhibited antinociceptive effect. 1,4-Androstadiene-$3{\beta},17{\beta}$-diol (DH-5, 100 mg/kg, $35.8{\pm}7.39$), $6{\alpha},7{\alpha}$-epoxy-1,4-androstadiene-3,17-dione (DH-4, 100 mg/kg, $32.6{\pm}5.50$) and $5{\alpha},6{\alpha}$-epoxy-17-oxo-androstan-$3{\beta}$-ol (DH-1, 100 mg/kg, $32.5{\pm}2.98$) were more effective than morphine (10 mg/kg, $30.6{\pm}0.5$). The analgesic effects of androstane derivatives on acetic acid writhing in mice were lower than aspirin. The androstane derivatives were less effective than ibuprofen at inhibiting effects on the carrageenin induced paw oedema. 4,6-Cholestadien-$3{\beta}$-ol (CH-5), $1{\alpha},2{\alpha}$-epoxy-4,6-cholestadien-$3{\beta}$-ol (CH-7) and $7{\alpha}$-hydroxy4-cholesten-3-one (CH-9) showed the decrease of serum triglyceride and total cholesterol levels in poloxamer P-407 injected rat.

Keywords

References

  1. Araghiniknam, M., Chung, S., Tresa, N.-W., Eskelson, C. and Watson, R. R. : Antioxidant activity of dioscorea and dehydroepiandrosterone (DHEA) in older humans. Life Sci. 59(11), 147 (1996)
  2. Aspinall, S. R., Stamp, S., Davison, A., Shenton, B. K. and Leonard, T. W. : The proliferative effects of 5-androstene-3p,17(3-diol and $5{\alpha}-dihydrotestosterone$ on cell cycle analysis and cell proliferation in MCF7, T47D and MDAMB231 breast cancer cell lines. J. Steroid Biochem. Mol. Biol. 88(1), 37 (2004) https://doi.org/10.1016/j.jsbmb.2003.10.011
  3. Maggiolini, M., Carpino, A., Bonofiglio, D., Pezzi, V, Rago, V, Marsico, S., Picard, D. and Ando, S. : The direct proliferative stimulus of dehydroepiandrosterone on MCF-7 breast cancer cells is potentiated by overexpression of aromatase. Mol. Cell Endocrinol. 184(1-2), 163 (2001)
  4. Gordon, G. B., Helzlsouer, K. J. and Comstock, G. W.: Serum levels of dehydroepiandrosterone and its sulfate and the risk of developing bladder cancer. Cancer Res. 51, 1366 (1991)
  5. Schulz, S., Klann, R. C, Schonfeld, S. and Nyce, J. W. : Mechanisms of cell growth inhibition and cell cycle arrest in human colonic adenocarcinoma cells by dehydroepiandrosterone: role of isoprenoid biosynthesis. Cancer Res. 52, 1372 (1992)
  6. Cleary, M. E, Shepherd, A. and Jenks, B. : Effect of DHEA of growth in lean and obese Zucker rats. J. Nutr. 114,1242 (1984)
  7. Hayashi, T., Esaki, T, Muto, E., Kano, H., Asai, Y, Thakur, N. K., Sumi, D., Jayachandrin, M. and Iquchi, A. : Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen : the possible role of nitric oxide. Arterioscler. Thromb. Vasc. Biol. 20(3), 782 (2000)
  8. Loria, R. M., Padgett, D. A. and Huynh, P. N. : Regulation of the immune response by dehydroepiandrosterone and its metabolites. J. Endocrinol. 150, S209 (1996)
  9. Frye, C. A., Van Keuren, K. R., Rao, P. N. and Erskine, M. S.: Analgesic effects of the neurosteroid $3{\alpha}-androstanediol$. Brain Res. 709, 1 (1996)
  10. Guggenheim, C. B. and Foster, H. G. Jr. : Serum cholesterol and perception of anger and sadness. Psychol. Rep. 77, 1343 (1995) https://doi.org/10.2466/pr0.1995.77.3.995
  11. Vevera, J., Fisar, Z., Kvasnicka, T, Zdenek, H., Starkova, L., Cestka, R. and Papezova, H. : Cholesterol-lowering therapy evokes time-limited changes in serotonergic transmission. Psychiatry Res. 133(2-3), 197 (2005) https://doi.org/10.1016/j.psychres.2004.11.005
  12. Easterman, A. L., Baum, H., Javitt, N. B. and Darlington, G. J.: 26-Hydroxycholesterol: regulation of hydroxymethylglutaryl CoA reductase activity in Chinese hamster ovary cell culture. J. Lipid Res. 24, 1304 (1983)
  13. Li, D. and Spencer, T. A. : Synthesis of $7{\beta}-hydroxy$ derivatives of regulatory oxysterols. Steroids 65, 529 (2000)
  14. Saucier, S. E., Kandutsch, A. A., Gayen, A. K., Swahn, D. K. and Spencer, T. A. : Oxysterol regulators of 3-hydroxy-3-methylglutaryl CoA reductase in liver. Effect of dietary cholesterol. J. Biol. Chem. 264, 6863 (1989)
  15. Taylor, E R., Kandutsch, A. A., Gayen, A. K., Nelson, J. A., Nelson, S. S., Phirwa, S. and Spencer, T. A.: 24,25-Epoxysterol metabolism in cultured mammalian cells and repression of 3-hydroxy-3-methylglutaryl CoA reductase. J. Biol Chem. 261, 15039 (1986)
  16. Ma, E. and Kim, E. : Epoxidation and reduction of DHEA, l,4,6-androstatriene-3,17-dione and 4,6-androstadiene-$3{\beta}$,$17{\beta}$-diol. Molecules 10, 572 (2005) https://doi.org/10.3390/10030572
  17. Ma, E., Kim, H. and Kim, E. : Epoxidation and reduction of cholesterol, l,4,6-cholestatrien-3-one and 4,6-cholestadien-$3{\beta}$-ol. Steroids 70, 245 (2005) https://doi.org/10.1016/j.steroids.2004.11.003
  18. Johnston, T. E and Palmer, W. K. : Mechanism of poloxamer 407-induced hypertriglyceridemia in the rat. Biochem. Pharmacol. 46, 1037 (1993)
  19. Korde, S. S., Baig, M. H., Desai, U. R. and Trivedi, G. K. : Differential behavior of (25R)-5,6-epoxyspirostan-$22{\alpha}$-O-$3{\beta}$,$4{\beta}$-ol and (25R)-5,6-epoxyspiro stan-$22{\alpha}$-O-$3{\beta}$,$4{\beta}$-diol toward Dowex. Steroids 61, 290 (1996)
  20. Woolfe, G. and MacDonald, A. D. : The evaluation of the analgesic action of pethidine hydrochloride (Demerol). J. Pharmacol. Exp. Ther. 80, 300 (1944)
  21. Whittle, B. A. : The use of changes in capillary permeability in mice to distinguish between narcotic and nonnarcotic analgesics. Br. J. Pharmacol. Chemother. 22, 246 (1964)
  22. Winter, C. A., Risley, E. A. and Nuss, G. W. : Carrageenin-induced edema hind paw of the rat as an assay for antiinflammatory drugs. Proc. Soc. Exp. Biol. Med. 111, 544 (1962)
  23. Richmond, W.: Use of cholesterol oxidase for assay of total and free cholesterol in serum by continuous flow analysis. Clin. Chem. 22, 1579 (1976)
  24. McGowan, M. W, Artiss, J. D., Stranbergh, D. R. and Zak, B. : A peroxidase coupled method for the colorimetric determination of serum triglycerides. Clin. Chem. 29, 538 (1983)
  25. Sandrini, M., Vitale, G. and Pini, L. A.: Central antinociceptive activity of acetylsalicylic acid is modulated by brain serotonin receptor subtypes. Pharmacology 65, 193 (2002) https://doi.org/10.1159/000056179
  26. Bulka, A., Wiesenfeld-Hallin, Z. and Xu, X. J. : Differential antinociception by morphine and methadone in two sub-strains of Spraque-Dawley rats and its potentiation by dextromethorphan. Brain Res. 942, 95 (2002)