All-<i>trans</i>-Configuration in <i>Zanthoxylum</i> Alkylamides Swaps the Tingling with a Numbing Sensation and Diminishes Salivation

Bader, Matthias; Stark, Timo D.; Dawid, Corinna; Lösch, Sofie; Hofmann, Thomas

doi:10.1021/jf500399w

Cited by 83 publications

(72 citation statements)

References 18 publications

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“…The huajiao/citric acid cluster is diffuse, with huajiao positioned along the anesthetizing/numbing, cooling axis and citric acid along the puckering, sour, astringent/drying axis. The placement of huajiao on the map and association with anesthetizing/numbing descriptions are expected, as this placement is consistent with prior reports that hydroxyl-alpha-sanshool (the compound primarily responsible for the sensation elicited by huajiao) and its derivatives elicit numbing and tingling sensations (Albin and Simons 2010; Bader et al 2014; Galopin et al 2004; Yang 2008; Yasuda et al 1982). Similarly, it is unsurprising that citric acid was described as puckering and sour.…”

Section: Discussionsupporting

confidence: 87%

Perceptual Mapping of Chemesthetic Stimuli in Naive Assessors

Byrnes

Nestrud²,

Hayes

2015

Chem. Percept.

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Chemesthetic compounds, responsible for sensations such as burning, cooling, and astringency, are difficult stimuli to work with, especially when the evaluation task requires retasting. Here, we developed a protocol by which chemesthetic compounds can be assessed using sorting. We compared the performance of two cohorts of untrained assessors on this task, one with nose clips and the other without. Similarity matrices were analyzed using multidimensional scaling (MDS) to produce perceptual maps for the two cohorts. Overall, the groupings from the nose open cohort tended to follow a biological basis, consistent with previous findings that suggest compounds that activate a common receptor will elicit similar sensations. The nose-open and nose-pinched cohorts generated significantly different maps. The nose-pinched cohort had a higher variance in the MDS solution than the nose-open group. While the nose-open cohort generated seven clusters, the nose-pinched cohort generated only two clusters, seemingly based on the ready identification of chemesthetic sensations or not. There was less consensus regarding the attributes used to describe the samples in the nose-pinched cohort than in the nose-open cohort as well, as this cohort collectively generated more attributes but fewer were significant in regression.

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Section: Discussionsupporting

confidence: 87%

Perceptual Mapping of Chemesthetic Stimuli in Naive Assessors

Byrnes

Nestrud²,

Hayes

2015

Chem. Percept.

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“…We addressed the question of whether it was plausible that KCNK channels could constitute a physiologically relevant target for the sensory active compounds present in black peppercorns. Prior research had demonstrated that pungent/tingling-sensing Zanthoxylum alkylamides, such as α-hydroxysanshool, which activates TRPV1 and TRPA1 channels (Sugai et al, 2005; Koo et al, 2007; Menozzi-Smarrito et al, 2009; Bader et al, 2014), additionally excite sensory neurons by inhibiting KCNK channels (Bautista et al, 2008). No similar evidence was available for exclusively pungent-sensing compounds on KCNK channels, as our previous experiments were limited to a heterologous system (Beltrán et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Pungent and Tingling Compounds from Piper nigrum L. on Background K+ Currents

et al. 2017

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Black peppercorns (Piper nigrum L.) elicit a pungent and tingling oral impression. Their pungency is partially explained by the agonist activity of some of their active principles, especially piperine, on TRP channels. However, we recently showed that piperine, as well as other pungent compounds, also possess a marked effect on two-pore domain (KCNK, K2P) K+ channels. Members of this family play a key role in maintaining the resting membrane potential of excitable cells. Interestingly, tingling compounds have been shown to induce neuronal excitation by inhibiting KCNK channels. We addressed the question of whether it was plausible that KCNK channels could constitute a physiologically relevant target for the sensory active compounds present in black peppercorns. Because previous studies have demonstrated that mouse trigeminal neurons respond to several pungent compounds, to which humans are also sensitive, we used a primary culture of mouse trigeminal neurons to investigate whether the effect of piperine on these cell types could also be mediated by KCNK channels. We observed that even in the presence of classical TRP-antagonists, piperine was still able to activate a fraction of trigeminal neurons. Furthermore, our results showed that piperine is capable of inducing neuronal depolarization by a mechanism that does not require extracellular Na+ or Ca2+. This depolarization was mediated by the inhibition of a background K+ conductance, most likely corresponding to the KCNK channels of the TASK subfamily. We then performed a screening with 12 other pungent and/or tingling chemosensates isolated from black peppercorns. These compounds were evaluated on Xenopus laevis oocytes expressing the human orthologues of KCNK3, KNCK9 and KCNK18, which we previously showed to be inhibited by piperine. Remarkably, almost all of the isolated chemosensates inhibited the basal activity of hKCNK3, with 1-(octadeca-2E,4E,13/12Z-trienoyl)pyrrolidine acting as one of the most potent natural blockers for hKCNK3 found to date. Our results suggest that KCNK channels, especially KCNK3, are likely to play a complementary role to TRP channels in the complex orosensory impression elicited by black peppercorns, while they also help to expand the pharmacological knowledge of KCNK channels.

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“…7) elicited the well-known tingling and paresthetic orosensation above threshold levels of 3.5-8.3 nmol/cm 2 . In contrast, the all-E configurated derivatives 59d and 74d induced a numbing and anesthetic sensation above thresholds of 3.9 and 7.1 nmol/cm 2 , respectively (Bader et al 2014). …”

Section: Structure-activity Relationshipsmentioning

confidence: 96%

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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All-trans-Configuration in Zanthoxylum Alkylamides Swaps the Tingling with a Numbing Sensation and Diminishes Salivation

Cited by 83 publications

References 18 publications

Perceptual Mapping of Chemesthetic Stimuli in Naive Assessors

Perceptual Mapping of Chemesthetic Stimuli in Naive Assessors

The Effect of Pungent and Tingling Compounds from Piper nigrum L. on Background K+ Currents

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

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