5-HT₃ Receptor Blocking Activity of Arylalkanes Isolated from the Rhizome of Zingiber officinale

Abstract

Different extracts (ethanolic, hexane, aqueous) of ginger (rhizomes of Zingiber officinale) and the essential oil were tested using [¹⁴C]guanidinium influx into N1E-115 cells and the isolated rat ileum in order to identify their activity in inhibiting 5-HT₃ receptor function. The hexane extract proved to be the most active and yielded upon bioassay-guided fractionation nine constituents: [6]-, [8]-, [10]-gingerols, [6]- and [8]-shogaols which were previously shown as active in vivo against cytotoxic drug-induced emesis; [4]-gingerol, [6]-gingerdiol, diacetyl-[6]-gingerdiol and [6]-dehydrogingerdione have not been previously tested for anti-emetic or 5-HT₃ receptor antagonistic effects. Even though the latter four compounds are only minor constituents, their identification contributed towards the characterisation of a structure-activity relationship of this class of compounds. The order of potency for the nine constituents in the N1E-115 cell system was [6]-gingerdiol ≈ diacetyl-[6]-gingerdiol ≈ [6]-dehydrogingerdione ≈ [6]-shogaol ≥ [8]-shogaol ≈ [8]-gingerol > [10]-gingerol ≥ [6]-gingerol > [4]-gingerol.

Key words

Zingiber officinale - Zingiberaceae - anti-emetic activity - 5-HT₃ receptor antagonists - N1E-115 cells - gingerol derivatives - SAR

References

• 1 Sharma S S, Kochupillai V, Gupta S K, Seth S D, Gupta Y K. Antiemetic efficacy of ginger (Zingiber officinale) against cisplatin-induced emesis in dogs.  J Ethnopharmacol. 1997;  57 93-6
• 2 Yamahara J, Rong H Q, Naitoh Y, Kitani T, Fujimura H. Inhibition of cytotoxic drug-induced vomiting in suncus by a ginger constituent.  J Ethnopharmacol. 1989;  27 353-5
• 3 Yang Y, Kinoshita K, Koyama K, Takahashi K, Tai T, Nunoura Y. et al . Novel experimental model using free radical-induced emesis for surveying anti-emetic compounds from natural sources.  Planta Med. 1999;  65 574-6
• 4 Kawai T, Kinoshita K, Koyama K, Takahashi K. Anti-emetic principles of Magnolia obovata bark and Zingiber officinale rhizome.  Planta Med. 1994;  60 17-20
• 5 Yang Y, Kinoshita K, Koyama K, Takahashi K, Kondo S, Watanabe K. Structure-antiemetic-activity of some diarylheptanoids and their analogues.  Phytomedicine. 2002;  9 146-52
• 6 Yamahara J, Qi Rong H, Iwamoto M, Kobayashi G, Matsuda H, Fujimura H. Active components of ginger exhibiting antiserotonergic action.  Phytother Res. 1989;  3 70-1
• 7 Boenisch H, Barann M, Graupner J, Gothert M. Characterization of 5-HT₃ receptors of N1E-115 neuroblastoma cells by use of the influx of the organic cation [¹⁴C]-guanidinium.  Br J Pharmacol. 1993;  108 436-42
• 8 Shoji N, Iwasa A, Takemoto T, Ishida Y, Ohizumi Y. Cardiotonic principles of ginger (Zingiber officinale Roscoe).  J Pharm Sci. 1982;  71 1174-5
• 9 Beilstein M DL. CrossFire Server Software 6.0, Database ‘BS0401PR’ with 8 932 531 compounds. Beilstein Data: Copyright © 1988 - 2004
• 10 Fleming S, Dyer C W, Eggington J. A convenient one-step gingerol synthesis.  Synth Commun. 1999;  29 1933-9
• 11 Kikuzaki H, Tsai S, Hakatani N. Gingerdiol related compounds from the rhizomes of zingiber officinale .  Phytochemistry. 1992;  31 1783-6
• 12 Kiuchi F, Iwakami S, Shibuya M, Hanaoka F, Sankawa U. Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids.  Chem Pharm Bull (Tokyo). 1992;  40 387-91
• 13 Pace J. Oral ingestion of encapsulated ginger and reported self-care actions for the relief of chemotherapy-associated nausea and vomiting.  Diss Abstr Int. 1987;  47 3297
• 14 Meyer K, Schwartz J, Crater D, Keyes B. Zingiber officinale (ginger) used to prevent 8-Mop associated nausea.  Dermatol Nurs. 1995;  7 242-4
• 15 Andrews P L, Rapeport W G, Sanger G. Neuropharmacology of emesis induced by anti-cancer therapy.  Trends Pharmacol Sci. 1988;  9 334-41
• 16 Huang Q R, Iwamoto M, Aoki S, Tanaka N, Tajima K, Yamahara J. et al . Anti-5-hydroxytryptamine3 effect of galanolactone, diterpenoid isolated from ginger.  Chem Pharm Bull (Tokyo). 1991;  39 397-9
• 17 Buchheit K H, Engel G, Mutschler E, Richardson B. Study of the contractile effect of 5-hydroxytryptamine (5-HT) in the isolated longitudinal muscle strip from guinea-pig ileum. Evidence for two distinct release mechanisms.  Naunyn Schmiedebergs Arch Pharmacol. 1985;  329 36-41
• 18 Carter D, Champney M, Hwang B, Eglen R M. Characterization of a postjunctional 5-HT receptor mediating relaxation of guinea-pig isolated ileum.  Eur J Pharmacol. 1995;  280 243-50
• 19 Yoshikawa M, Hatakeyama S, Chatani N, Nishino Y, Yamahara J. Qualitative and quantitative analysis of bioactive principles in Zingiberis Rhizoma by means of high performance liquid chromatography and gas liquid chromatography. On the evaluation of Zingiberis Rhizoma and chemical change of constituents during Zingiberis Rhizoma processing.  Yakugaku Zasshi. 1993;  113 307-15
• 20 Barann M, Gothert M, Bruss M, Boenisch H. Inhibition by steroids of [¹⁴C]-guanidinium flux through the voltage-gated sodium channel and the cation channel of the 5-HT₃ receptor of N1E-115 neuroblastoma cells.  Naunyn Schmiedebergs Arch Pharmacol. 1999;  360 234-41
• 21 Barann M, Gothert M, Fink K, Boenisch H. Inhibition by anaesthetics of ¹⁴C-guanidinium flux through the voltage-gated sodium channel and the cation channel of the 5-HT₃ receptor of N1E-115 neuroblastoma cells.  Naunyn Schmiedebergs Arch Pharmacol. 1993;  347 125-32