Adenosine A₁ Receptor Binding Activity of Methoxy Flavonoids from Orthosiphon stamineus

Abstract

Orthosiphon stamineus Benth. (Orthosiphon grandiflorus Bold. or Clerodendranthus spicatus Thunb.) is an Indonesian medicinal herb traditionally used for diseases such as hypertension, diabetes, and kidney stones. Despite the importance of this last application, there are very few reports on it. Diuretic action is an important factor in kidney stone treatment, as an increase in the volume of fluid flowing through the kidney will help to dissolve the stones, assist their passing to avoid further retention, and flush out the deposits. Among the diverse roles of adenosine A₁ receptor antagonists in renal protection, many studies have shown that they can induce diuresis and sodium excretion. A bioassay-guided fractionation of a methanol-water extract of Orthosiphon stamineus leaves using the adenosine A₁ receptor binding assay resulted in the isolation of seven methoxy flavonoids as active ligands with K _i values in the micromolar range. The Hill slope values are not significantly different from unity (within 0.9 – 1.4), which indicates the antagonist effect to A₁-R. The results of this study thus provide a scientific foundation for the traditional use of Orthosiphon stamineus in kidney stone treatment, as the affinity of the active compounds isolated from it as adenosine A₁ receptor ligands allows them to be associated with diuretic activity, which is one possible treatment for renal lithiasis.

Abbreviations

CPA:N⁶-cyclopentyladenosine

DPCPX:8-cyclopentyl-1,3-dipropylxanthine

GFR:glomerular filtration rate

RBF:renal blood flow

Orthosiphon stamineus - Lamiaceae - adenosine A₁ receptor - methoxy flavonoid - diuretic - kidney stone

References

• 1 Akowuah G A, Zhari I, Norhayati I, Sadikun A, Khamsah S M. Sinensetin, eupatorin, 3′-hydroxy-5, 6, 7, 4′-tetramethoxyflavone and rosmarinic acid contents and antioxidative effect of Orthosiphon stamineus from Malaysia.  Food Chem. 2004;  87 559-66
• 2 Awale S, Tezuka Y, Banskota A H, Adnyana K, Kadota S. Highly-oxygenated isopimarane-type diterpenes from Orthosiphon stamineus of Indonesia and their nitric oxide inhibitory activity.  Chem Pharm Bull. 2003;  51 268-75
• 3 Stampoulis P, Tezuka Y, Banskota A H, Tran K Q, Saiki I, Kadota S. Staminol A, a novel diterpene from Orthosiphon stamineus. .  Tetrahedron Lett. 1999;  40 4239-42
• 4 Masuda T, Masuda K, Shiragami S, Jitoe A, Nakatani N. Orthosiphol A and B, novel diterpenoid inhibitors of TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation, from Orthosiphon stamineus. .  Tetrahedron. 1992;  48 6787-92
• 5 Hussein A A, Meyer J JM, Jimeno M L, Rodriguez B. Bioactive diterpenes from Orthosiphon labiatus and Salvia africana-lutea. .  J Nat Prod. 2007;  70 293-5
• 6 Yoshimura H, Sugawara K, Saito M, Saito S, Murakami S, Miyata N. et al . In vitro TGF-β1 antagonistic activity of ursolic and oleanolic acids isolated from Clerodendranthus spicatus. .  Planta Med. 2003;  69 673-5
• 7 Malterud K E, Hanche-Olsen I M, Smith Kielland I. Flavonoids from Orthosiphon spicatus. .  Planta Med. 1989;  55 569-70
• 8 Englert J, Harnischfeger G. Diuretic action of aqueous Orthosiphon extract in rats.  Planta Med. 1992;  58 237-8
• 9 Poulsen S A, Quinn R J. Adenosine receptors: new opportunities for future drugs.  Bioorg Med Chem. 1998;  6 619-41
• 10 Chang L CW, Brussee J, Ijzerman A P. Non-xanthin antagonist for the adenosine A₁ receptor.  Chem Biodivers. 2004;  1 1591-626
• 11 Modlinger P S, Welch W J. Adenosine A₁ receptor antagonists and the kidney.  Curr Opin Nephrol Hypertens. 2003;  12 497-502
• 12 Gohel M DI, Wong S P. Chinese herbal medicines and their efficacy in treating renal stones.  Urol Res. 2006;  34 365-72
• 13 Speilman W S, Arend L J. Adenosine receptors and signaling in the kidney.  Hypertension. 1991;  17 117-30
• 14 Vu C B, Kiesman W F, Conlon P R, Lin K C, Tam M, Petter R C. et al . Tricyclic imidazoline derivatives as potent and selective adenosine A₁ receptor antagonists.  J Med Chem. 2006;  49 7132-9
• 15 Givertz M M, Massie B M, Fields T K, Pearson L L, Dittrich H C. The effects of KW-3902, an adenosine A₁-receptor antagonist, on diuresis and renal function in patients with decomposed heart failure and renal importance or diuretic resistance.  J Am Coll Cardiol. 2007;  50 1551-60
• 16 Chang L CW, Spanjersberg R F, von Frijtag Drabbe Kunzel J K, Mulder-Krieger T, van den Hout G, Beukers M W. et al . 2,4,6-Trisubstituted pyrimidines as a new class of selective adenosine A₁ receptor antagonists.  J Med Chem. 2004;  47 6529-40
• 17 Dalpiaz A, Townsend-Nicholson A, Beukers M W, Schofield P R, Ijzerman A P. Thermodynamics of full agonist, partial agonist, and antagonist binding to wild-type and mutant adenosine A₁ receptors.  Biochem Pharmacol. 1998;  56 1437-45
• 18 Chen Y C, Prusoff W H. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (I ₅₀) of an enzymatic reaction.  Biochem Pharmacol. 1973;  22 3099-108
• 19 Moro S, van Rhee M, Sanders L H, Jacobson K A. Flavonoid derivatives as adenosine receptor antagonists: A comparison of the hypothetical receptor binding site based on a comparative molecular field analysis model.  J Med Chem. 1998;  41 46-52
• 20 Ji X -D, Melman N, Jacobson K A. Interactions of flavonoids and other phytochemicals with adenosine receptors.  J Med Chem. 1996;  39 781-8
• 21 Inuma M, Matsuura S, Kusuda K. ¹³C-NMR spectral studies on polysubstituted flavonoids. I. ¹³C-NMR spectra of flavones.  Chem Pharm Bull. 1980;  28 708-16
• 22 Chari V M, Graye-Barkmeijer R J, Harborne J B, Osterdahl B G. An acylated allose-containing 8-hydroxyflavone glycoside from Veronoca filiformis. .  Phytochemistry. 1981;  20 1977-9
• 23 Kupchan S M, Sigel C W, Knox J R, Udayamurthy M S. Eupatin and eupatoretin, two cytotoxic flavonols from Eupatorium semiserratum. .  J Org Chem. 1969;  34 1460-3
• 24 Ingkaninan K, Ijzerman A P, Verpoorte R. Luteolin, a compound with adenosine A₁ receptor-binding activity, and chromone and dihydronaphthalenone constituents from Senna siamea. .  J Nat Prod. 2000;  63 315-7
• 25 Alexander S PH. Flavonoids as antagonist at A₁ adenosine receptors.  Phytother Res. 2006;  20 1009-12
• 26 Gürocak S, Küpeli B. Consumption of historical and current phytotherapeutic agents for urolithiasis: a critical review.  J Urol. 2006;  176 450-5
• 27 Wen X, Walle T. Methylated flavonoids have greatly improved intestinal absorption and metabolic stability.  Drug Metab Disp. 2006;  34 1786-92