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Inhibitory Effects of Furoquinoline Alkaloids from Melicope confusa and Dictamnus albus against Human Phosphodiesterase 5 (hPDE5A) In Vitro  

Nam Kung-woo (Jung-San Biotechnology Institute, Natural Products Research Institute, Seoul National University, College of Pharmacy)
Je Kang-Hoon (Natural Products Research Institute, Seoul National University, College of Pharmacy)
Shin Young-Jun (Jung-San Biotechnology Institute)
Kang Sam Sik (Natural Products Research Institute, Seoul National University, College of Pharmacy)
Mar Woongchon (Natural Products Research Institute, Seoul National University, College of Pharmacy)
Publication Information
Archives of Pharmacal Research / v.28, no.6, 2005 , pp. 675-679 More about this Journal
Abstract
Eight furoquinoline alkaloids were purified from two plants belonging to the Rutaceae family. Kokusaginine. skimmianine, evolitrine, and confusameline were purified from Melicope confusa, and haplopine, robustine, dictamine, and $\gamma$-fagarine from Dictamnus albus. In this study, the eight furoquinoline alkaloids were examined for inhibitory potency against human phos-phodiesterase 5 (hPDE5A) in vitro. DNA encoding the catalytic domain of human PDE5A was amplified from the mRNA of T24 cells by RT-PCR and was fused to GST in an expression vector. GST-tagged PDE5A was then purified by glutathione affinity chromatography and used in inhibition assays. Of the eight alkaloids, $\gamma$-fagarine was the most potent inhibitor of PDE5A, and its single methoxy group at the C-8 position was shown to be critical for inhibitory activity. These results clearly illustrate the relationship between PDE5A inhibition and the methoxy group position in furoquinoline alkaloids.
Keywords
Furoquinoline alkaloids; cGMP; Smooth muscle; hPDE5A;
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1 Francis, S. H., Bessay, E. P., Kotera, J., Grimes, K. A., Liu, L., Thompson, W. J., and Corbin, J. D., Phosphorylation of isolated human phosphodiesterase-5 regulatory domain induces an apparent conformational change and increases cGMP binding affinity. J. Biol. Chem., 277, 47581-47587 (2002)   DOI   ScienceOn
2 Hirose, R., Okumura, H., Yoshimatsu, A., Irie, J., Onoda, Y., Nomoto, Y., Takai, H., Ohno, T., and Ichimura, M., KF31327, a new potent and selective inhibitor of cyclic nucleotide phosphodiesterase 5. Eur. J. Pharmacol., 431, 17-24 (2001)   DOI   ScienceOn
3 Natochin, M. and Artemyev, N. O., An interface of interaction between photoreceptor cGMP phosphodiesterase catalytic subunits and inhibitory gamma subunits. J. Biol. Chem., 271, 19964-19969 (1996)   DOI   ScienceOn
4 Tejada, I. S., Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat. Int. J. Impot. Res., 16, S40-S42 (2004)   DOI   ScienceOn
5 Turbo, I. V., Haik, T. L., McAllister-Lucas, L. M., Burns, F., Francis, S. H., and Corbin, J. D., Identification of key amino acids in a conserved cGMP-binding site of cGMP-binding phosphodieaterases. A putative NKXnD motif for cGMP biding. J. Biol. Chem., 271, 22240-22244 (1996)   DOI   ScienceOn
6 Fink, T. L., Francis, S. H., Beasley, A., Grimes, K. A., and Corbin, J. D., Expression of an active, monomeric catalytic domain of the cGMP-binding cGMP-specific phosphodiesterase (PDE5). J. Biol. Chem., 274, 34613-34620 (1999)   DOI   ScienceOn
7 Blount, M. A., Beasley, A., Zoraghi, R., Sekhar, K. R., Bessay, E. P., Francis, S. H., Corbin, J. D., Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation. Mol. Pharmacol., 66, 144-152 (2004)   DOI   ScienceOn
8 Mehats, C., Andersen, C. B., Filopanti, M., Jin, S. L., and Conti, M., Cyclic nucleotide phosphodieterase and their role in endocrine cell signaling. Trends Endocrinol. Metab., 13, 29-35 (2002)   DOI   ScienceOn
9 Uckert, S., Kuthe, A., Stief, C. G., and Jonas, U., Phosphodiesterase isoenzymes as pharmacological targets in the treatment of male erectile dysfunction. World J. Urol., 19, 14-22 (2001)   DOI   ScienceOn
10 Turko, I. V., Ballard, S. A., Francis, S. H., and Corbin, J. D., Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type5) by sildenafil and related compounds. Mol. Pharmacol., 56, 124-130 (1999)   DOI
11 Sausbier, M., Schubert, R., Voigt, V., Hirneiss, C., Pfeifer, A., Korth, M., Kleppisch, T., Ruth, P., and Hormann, F., Mechanisms of NO/cGMP-dependent vasorelaxation. Circ. Res., 87, 825-830 (2000)   DOI   ScienceOn
12 Crocker, I. C. and Townley, R. G., Therapeutic potential of phosphodiesterase 4 inhibitors in allergic diseases. Drugs Today (Barc), 35, 519-535 (1999)   DOI
13 Boolell, M., Allen, M. J., Ballard, S. A., Gepi-Attee, S., Muirhead, G. J., Naylor, A. M., Osterloh, I. H., Gingell, C., Sildenafill: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int. J. Impot. Res., 8, 47-52 (1996)
14 Bradford, M. M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 72, 248-254 (1976)   DOI   PUBMED   ScienceOn
15 Rybalkin, S. D., Rybalkina, I. G., SHimizu-Albergine, M., Tang, X. B., and Beavo, J. A., PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO Journal, 223, 469-478 (2003)   DOI   PUBMED   ScienceOn
16 Lin, C. S., Chow, S., Lau, A., Tu, R., and Lue, T. F., Human PDE5A gene encodes three PDE5 isoforms from two alternate promoters. Int. J. Impot. Res., 14, 15-24 (2002)   DOI   ScienceOn
17 White, D. G. and Martin, W., Differential control and calciumdependence of production of endothelium- derived relaxing factor and prostacyclin by pig arotic ndothelial cells. Br. J. Pharmacol., 97, 683-690 (1989)   DOI   ScienceOn
18 Chen, Y., Traverse, J. H., Hou, M., Li, Y., Du, R., and Bache, R. J., Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure. Am. J. Physiol. Heart Circ. Physiol., 284, H1513-H1520 (2003)   DOI
19 Wyatt, T. A., Naftilan, A. J., Francis, S. H., and Corbin, J. D., ANF elicits phosphorylation of the cGMP phosphodiesterase in vascular smooth muscle cells. Am. J. Physiol., 274, H448-H455 (1998)
20 Funayama, S., Tanaka, R., Kumekawa, Y., Noshita, T., Mori, T., Kashiwagura, T., and Murata, K., Rat small intestine muscle relaxation alkaloids from Orixa japonica leaves. Biol. Pharm. Bull., 24, 100-102 (2001)   DOI   ScienceOn
21 Wang, M., Urenjak, J., Fedele, E., and Obrenovitch, T. P., Effects of phosphodiesterase inhibition on cortical spreading depression and associated changes in extracellular cyclic GMP. Biochem. Pharmacol., 67, 1619-1627 (2004)   DOI   ScienceOn
22 Chen, Z., Zhang, J., and Stamler, J. S., Identification of the enzymatic mechanism of mitroglycerin bioactivation. Proc. Natl. Acad. Sci. U.S.A., 99, 8306-8311 (2002)   DOI   ScienceOn
23 Schmit, D., Dent, G., and Rabe, K. F., Selective phosphodiesterase inhibitors for the treatment of bronchial asthma and chronic obstructive pulmonary disease. Clin. Exp. Allergy, 29, 99-109 (1999)
24 Lacas, K. A., Pitari, G. M., Kazerounian, S., Ruiz-Stewart, I., Park, J., Schulz, S., Chepenik, K. P., and Waldman, S., Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev., 52, 385-414 (2000)
25 Kim, D. K., Lee, J. Y., Lee, N., Ryu, D. H., Kim, J. S., Choi, J.Y., Ryu, J. H., Kim, N. H., Im, G. H., Choi, W. S., and Kim, T. K., Synthesis and phosphodiesterase inhibitory activity of new sildenafil analogues containing a carboxylic acid group in the 5`-sulfonamide moiety of a phenyl ring. Bioorg. Med. Chem., 9, 3013-3021 (2001)   DOI   ScienceOn