Structure-activity relationships of trigeminal effects for artificial and naturally occurring alkamides related to spilanthol

Ley, Jakob P.; Krammer, Gerhard; Looft, J.; Reinders, Gerald; Bertram, Heinz‐Jürgen

doi:10.1016/s0167-4501(06)80006-3

Cited by 23 publications

(14 citation statements)

References 3 publications

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“…Various trigeminal effects for artificial and naturally occurring alkamides related to spilanthol (92a) were reported (Ley et al 2006a). From 26 derivatives it was shown that 92a, having one Z-double bond, was the most active tingling and saliva-inducing compound.…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Alkamides: a critical reconsideration of a multifunctional class of unsaturated fatty acid amides

Greger

2015

Phytochem Rev

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Alkamides are natural products formed by connecting straight-chain, mostly unsaturated, aliphatic acids with various amines by an amide linkage. More than 300 derivatives are known from eight plant families consisting of various combinations of 200 acids with 23 amines. Apart from a few saturated derivatives alkamides with unsaturated acid parts are grouped into compounds with purely olefinic patterns and those with olefinic and acetylenic linkages. Derived from C 18 oleic acid the acid parts are modified either by chain elongations to C 28 or by oxidative shortenings to C 4 acid residues. Substrate and regiospecific desaturases and acetylenases are responsible for their characteristic patterns of unsaturation. Amine parts are derived from various amino acids by decarboxylation. Beside the widespread isobutylamines alkamides with six-and five-membered ring amines and those with phenylalanine derived amines are characteristic for the Asteraceae and Piperaceae while benzylamines are restricted to the Brassicaceae. Within the Asteraceae 2-methylbutylamine distinguishes the tribe Heliantheae from Anthemideae characterized by ring amines. Alkamides with elongated olefinic acid parts are mainly found in Piperaceae and Brassicaceae while acetylenic acid parts are typical for Asteraceae. A wide variety of biological activities ranges from the characteristic pungent/ tingling property and high insecticidal toxicity to significant antifungal, antibacterial, antiprotozoal, molluscicidal, cercaricidal, and acaricidal activity. They also act as plant growth-promoting substances. Position and stereochemistry of the double bonds are essential for the different qualities of the pungent taste. Medically alkamides possess anti-inflammatory and analgesic properties and are responsible for immunomodulatory and cannabinomimetic effects.

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Section: Structure-activity Relationshipsmentioning

confidence: 99%

Alkamides: a critical reconsideration of a multifunctional class of unsaturated fatty acid amides

Greger

2015

Phytochem Rev

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“…In addition to their effects on cytokine and chemokine production, alkylamides, including spilanthol and sanshool, have been linked to the tingling, analgesic activity of extracts made from alkylamide-producing plants such as E. purpurea, A. oleracea and Z. americanum (Albin and Simons, 2010; Bryant and Mezine, 1999; Ley et al, 2006). The numbing effects of alkylamides have been linked to activation of the capsaicin receptor, TRPV1 (Sugai et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Mast cell degranulation and calcium influx are inhibited by an Echinacea purpurea extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide

Gulledge

Collette

Mackey

et al. 2018

Journal of Ethnopharmacology

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Ethnopharmacological relevance Native Americans used plants from the genus Echinacea to treat a variety of different inflammatory conditions including swollen gums, sore throats, skin inflammation, and gastrointestinal disorders. Today, various Echinacea spp. preparations are used primarily to treat upper respiratory infections. Aim of the study The goal of this study was to evaluate the effects of an ethanolic E. purpurea (L) Moench root extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide (A15) on mast cells, which are important mediators of allergic and inflammatory responses. Inhibition of mast cell activation may help explain the traditional use of Echinacea. Materials and methods A15 was evaluated for its effects on degranulation, calcium influx, cytokine and lipid mediator production using bone marrow derived mast cells (BMMCs) and the transformed rat basophilic leukemia mast cell line RBL-2H3. Methods included enzymatic assays, fluorimetry, ELISAs, and microscopy. A root extract of E. purpurea, and low and high alkylamide-containing fractions prepared from this extract, were also tested for effects on mast cell function. Finally, we tested A15 for effects on calcium responses in RAW 264.7 macrophage and Jurkat T cell lines. Results A15 inhibited ß-hexosaminidase release from BMMCs and RBL-2H3 cells after treatment with the calcium ionophore A23187 by 83.5% and 48.4% at 100 μM, respectively. Inhibition also occurred following stimulation with IgE anti-DNP/DNP-HSA. In addition, A15 inhibited 47% of histamine release from A23187-treated RBL-2H3 cells. A15 prevented the rapid rise in intracellular calcium following FcεRI crosslinking and A23187 treatment suggesting it acts on the signals controlling granule release. An E. purpurea root extract and a fraction with high alkylamide content derived from this extract also displayed these activities while fractions with little to no detectable amounts of alkylamide did not. A15 mediated inhibition of calcium influx was not limited to mast cells as A23187-stimulated calcium influx was blocked in both RAW 264.7 and Jurkat cell lines with 60.2% and 43.6% inhibition at 1 min post-stimulation, respectively. A15 also inhibited the release of TNF-α, and PGE2 to a lesser degree, following A23187 stimulation indicating its broad activity on mast cell mediator production. Conclusions These findings suggest that Echinacea extracts and alkylamides may be useful for treating allergic and inflammatory responses mediated by mast cells. More broadly, since calcium is a critical second messenger, the inhibitory effects of alkylamides on calcium uptake would be predicted to dampen a variety of pathological responses, suggesting new uses for this plant and its constituents.

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“…Recently, oleocanthal from olive oil has been identified which elicits an irritant sensation sensed primarily from the pharynx (Beauchamp et al, 2005; Peyrot des Gachons et al, 2011). Other chemesthetic sensations include (a) pungency from ethanol (Green 1988;Prescott and Swain-Campbell 2000), cinnamic aldehyde (Prescott and Swain-Campbell 2000;Klein et al, 2011) and zingerone (Prescott and Stevenson 1996a;, (b) cooling from menthol (Eccles 1994;Cliff and Green 1994;1996) and other compounds including icillin (Wei and Seid 1983), WS-12 (Sherkheli et al, 2010), WS-23 (Serkheli et al, 2010) and a recently identified high-potency synthetic compound that elicits a strong cooling sensation of long duration (Furrer et al, 2008), (c) warming from camphor (Green 1990;Moqrich 2005) and (d) tingling from alpha-hydroxy-sanshool (Bryant and Mezine 1999;Albin and Simons 2010) or spilanthal (Ley et al, 2006), unique compounds derived from the sechuan peppercorn and jambu fruit, respectively.…”

Section: A)mentioning

confidence: 99%

Trigeminal Chemesthesis

Cometto‐Muñiz

Simons

2015

Handbook of Olfaction and Gustation

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Structure-activity relationships of trigeminal effects for artificial and naturally occurring alkamides related to spilanthol

Cited by 23 publications

References 3 publications

Alkamides: a critical reconsideration of a multifunctional class of unsaturated fatty acid amides

Alkamides: a critical reconsideration of a multifunctional class of unsaturated fatty acid amides

Mast cell degranulation and calcium influx are inhibited by an Echinacea purpurea extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide

Trigeminal Chemesthesis

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