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Review

Alkamides in Zanthoxylum Species: Phytochemical Profiles and Local Anesthetic Activities

by
I-Cheng Lu
1,2,
Pin-Yang Hu
1,
Chia-Heng Lin
1,
Lin-Li Chang
3,4,5,
Hung-Chen Wang
6,
Kuang-I Cheng
1,2,
Tz-Ping Gau
1,* and
Kai-Wei Lin
1,*
1
Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan
2
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
3
Department of Microbiology and Immunology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
4
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
5
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan
6
Department of Neurosurgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 833253, Taiwan
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(22), 12228; https://doi.org/10.3390/ijms252212228
Submission received: 5 October 2024 / Revised: 4 November 2024 / Accepted: 12 November 2024 / Published: 14 November 2024
(This article belongs to the Special Issue Molecular Studies of Natural Compounds and Plant Extracts—2nd Edition)
Browse Figures
Review Reports Versions Notes

Abstract

:
Zanthoxylum species have long been utilized in traditional medicine; among their various properties, they provide an analgesic effect. Central to this medicinal application are alkamides, a class of alkaloids characterized by their unsaturated fatty acid chains. These compounds are particularly noted for their distinctive alleviation of tingling and numbing effects, which are beneficial in dental pain management and local anesthesia. This review synthesizes the existing phytochemical research on alkamides derived from 11 Z. species, focusing on their chemical properties, pharmacodynamics and clinical implications. The analysis includes an examination of the structure–activity relationships (SARs), pharmacokinetics and mechanisms by which these compounds modulate sensations such as pungency and numbness, contributing to their analgesic and local anesthetic efficacy. This systemic review identifies significant research gaps, including the need for comprehensive evaluations of alkamide efficacy, detailed explorations of their pharmacological mechanisms and expanded clinical applications. These areas represent key opportunities for future investigations to enhance the understanding and utilization of alkamides in medical treatments.

Graphical Abstract

1. Introduction

Plant-derived sources have long been utilized for nutrients and medicines to treat diseases and to nourish health care in cultures worldwide. Moreover, bioactive compounds derived from plants serve as templates and provide structural designs for medicinal chemistry. Species of the genus Zanthoxylum L., belonging to the Rutaceae family, are distributed in tropical and subtropical regions, with the majority found in Asia, the Americas and Africa [1,2,3]. The ethnobotanical and biological reports indicate that the Zanthoxylum (Z.) species are traditionally used in managing various health conditions [4,5]. Secondary metabolites from Z. species extract have exhibited several pharmacological activities such as antioxidant, analgesic and anti-inflammatory activities, along with modulatory effects against obesity and diabetes [6,7,8,9]. Specifically, many species of Z. species distributed in tropical and subtropical regions are utilized for pain relief in relation to toothaches and post-operative pain, including Z. nitidum (Roxb.) DC. [10], Z. zanthoxyloides Lam [11,12,13,14], Z. schinifolium [15], Z. elephantiasis [16], Z. riedelianum Engl. [17], Z. Americanum Mill. [18], Z. bungeanum Maxim. [19], Z. gilletii (De Wild) P.G. Waterman [20], Z. chalybeum Engl. [21], Z. oxyphyllum Edgew. [22] and Z. heitzii (Aubrév. and Pellegr.) P.G. Waterman [23]. Those studies, mentioning pain attenuation in traditional uses, indicate that Z. species can be associated with potential sources for the drug development of local anesthetics.
The phytochemical profile of Z. species is diverse, encompassing terpenes, flavonoids, coumarins, phenolic acids and alkaloids. [4,5]. Among the alkaloids, alkamides represent a special class of bioactive constituents, characterized by straight-chain, unsaturated fatty acids linked via an amide bond to various amines, forming distinctive natural products [24,25]. Previous studies have revealed that alkamides are mostly found in the Z. species with, consequently, the traditional use of such Z. species herbs due to being rich in alkamides [26,27,28]. Alkamides exhibit a broad spectrum of biological activities, including antifungal, antibacterial, immunomodulatory, antidiabetic, anti-inflammatory, analgesic and neuroprotective effects. [29,30,31,32,33,34,35]. The unique tingling and numbing sensations in Z. species are attributed to the plants containing a collection of alkamides [25]. Furthermore, alkamide extracts or whole plants rich in alkamides are used in the treatment of toothaches or as anesthetics [36,37]. Previous reviews have shown that a series of alkamides in the genus Z. exhibit numbing and tingling sensations in sensory neurons [38], while a series of reviews reported that the alkamides from Z species or other plants caused numbing sensations and analgesic effects [24,28,39].
This review aims at providing a systematic and updated analysis of alkamides from 11 Z. species, focusing on their phytochemistry, pharmacological actions, pharmacokinetics and clinical applications with particular emphasis focused on the potential of these compounds as local anesthetics in the process of examining their sensory and analgesic effects. By synthesizing current knowledge and identifying research gaps, this review seeks to guide future investigations into the development of alkamides as potential local anesthetics.

2. Phytochemistry

2.1. Chemical Properties and Metabolism in the Plants

Alkamides are widely distributed in plants and are structurally related to N-acyl-L-homoserine lactones (AHLs) found in Gram-negative bacteria, as well as to N-acylethanolamines (NAEs) found in plants and mammals [40]. Accordingly, these compounds contain a fatty acid tail, which comprises saturated or unsaturated carbon chains with lengths ranging from C8 to C18 combined with an amide group and a variable headgroup. The olefinic double bonds of alkamides display E or Z forms depending on whether the higher priority groups (methylene) on both carbons of the double bond are on opposite sides or the same side, respectively. The characteristics of E/Z isomers, including the level of saturation, number of carbon atoms and stereochemistry, serve as chemical taxonomic criteria for different plant families [40].
The chemical structure of the alkamide family is unstable and sensitive to oxygen, light and heat due to the presence of unsaturated fatty acids containing olefinic bonds [41]; for example, the content of sanshool alkamides in an aqueous solution at pH 7.0 was reduced by 50% at room temperature over four weeks. These compounds are also susceptible to degrade at high temperatures, and an 80% ethanolic solution containing 200 ppm of alkamide exposed to ultraviolet (UV) light completely disappeared within four hours [42]. The double-bonded part of the alkamides might undergo changes under ultraviolet B (UVB) irradiation, leading to the interconversion of chemical structures [42]. A previous study tried to evaluate the degradation of alkamides in plant extracts under different storage conditions. Alkamides in DMSO solution degrade more slowly than in dry films, and, if alkamides are combined with phenolic acids acting as antioxidants in dry films, the degradation appears slower than that of alkamides with phenolic acids in DMSO solution [43]. Based on the above studies, this indicates that pure alkamides should be kept in solvents (except for acidic solutions). Low temperature and protection from light irradiation are essential for the storage of pure alkamides.
The alkamides produced in plants are usually responsive to environmental stress and promote plant growth. In plants, alkamides are secondary metabolites that exhibit a chemical defense against microbial and herbivorous predators [44]. The related metabolic pathways, dependent on phytohormones, lead to the expression of defense-related genes and the production of antimicrobial secondary metabolites [45]. Studies on alkamide generation and accumulation in Z. species have demonstrated that ZbFAD2 and ZbFAD3 are vital alkamide biosynthesis enzymes in Z. bungeanum via the promotion and regulation of the production of alkamides [46]. In plant development, alkamides produce unique stimulatory effects to control differentiation processes during plant growth through interaction with the cytokines in the signaling pathway [47]. Alkamides can also regulate NO production to promote lateral and adventitious root formation at various stages of Arabidopsis explant development [48].

2.2. Alkamides Extraction, Isolation and Structure Elucidation

Extraction is the initial stage in the process of isolating compounds from plant materials, and various methods of plant extraction can be tailored to target specific phytoconstituents and structures. The temperature and physicochemical conditions of extraction methods, which include maceration, infusion, decoction, Soxhlet extraction, counter-current extraction, sonication, supercritical fluid extraction, hydrodistillation, microwave-assisted extraction and ultrasound-assisted extraction, are chosen based on the constituents and properties of the plants involved [49,50].
Various solvent systems such as hexane, chloroform, ethyl acetate, ethanol and methanol are commonly employed for extracting alkamides from plant materials. Among these, chloroform is the most suitable solvent system, and, although both methanol and ethanol have also been used [40], studies have shown that water, methanol and ethanol extracts of Z. bungeanum tend to contain higher concentrations of alkamides compared to extracts obtained using other solvent systems. These three solvent extracts in particular are noted for their significant content of major alkamides such as ZP-amide C and ZP-amide D, suggesting that water, methanol and ethanol are effective solvents for extracting these specific alkamides from Z. bungeanum [51], with two previous studies demonstrating that ZP-amide C and ZP-amide D were isolated from the methanol extract of Z. piperitum [52], while 70% ethanol extract was used as solvent to extract and separate the alkamides from Z. bungeanum pericarps [53].
Chemical detection and identification of the structural characterization of compounds is a significant challenge in natural product research. Various solid-phase chromatography techniques play a crucial role in separating and analyzing these compounds. Coating materials used in chromatography assays such as thin-layer chromatography (TLC), column chromatography (CC), flash chromatography (FC), size-exclusion chromatography (SEC), medium-pressure liquid chromatography (MPLC) and high-performance liquid chromatography (HPLC) have all been successfully employed for separating natural products with similar structures [54].
Isolating and purifying alkamides from plants poses challenges primarily due to their structural similarity and tendency to exist as racemic mixtures. The structural similarity among alkamides makes it difficult to separate them using conventional purification methods; additionally, their racemic nature further complicates the isolation process because enantiomers (mirror-image forms) have identical physical and chemical properties, making it challenging to distinguish and separate them [24,55]. To overcome these challenges, chromatography-coated materials suited to a special structure are necessary, such as chiral chromatography, which can separate enantiomers based on their stereochemistry. For Z. bungeanum, two alkamide enantiomers were successfully isolated by preparative HPLC with a chiral column from a racemic mixture [56]. In order to confirm the structure of pure compounds obtained through the separation process, spectroscopic analysis, including Fourier-transform infrared spectroscopy (FTIR), Ultraviolet–visible spectroscopy (UV–Vis), nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) are used for structural elucidation. The circular dichroism (CD) spectrum combined with calculated electronic circular dichroism (ECD) and optical rotation are applied for absolute configurations of alkamides.
To date, about 65 alkamides have been isolated and identified from eleven Z. species. This review presents the phytochemical studies of alkamides obtained from 1957 to 2022. Their structures are shown in Figure 1, Figure 2, Figure 3 and Figure 4.

2.2.1. Alkamides from Zanthoxylum piperitum DC

The α-sanshool (1) isolated from a light petroleum extract of the ground bark of Z. piperitum through column chromatography on neutral alumina was the first alkamide obtained from Z. species [57], while Hydroxy-α-sanshool (2), β-sanshool (3) and (2E,4E,8E,10E,12E)-N-Isobutyl-2,4,8,10,12-tetradecapentaenamide (named δ-sanshool) (4) were isolated from a CHCl3 extract of the bark of Z. piperitum through normal-phase HPLC [58,59]. Hydroxy-ε-sanshool (5) was isolated from the seed of Z. piperitum by C18 reversed-phase HPLC using 30% aqueous MeOH [60], where 2 and 5 revealed a hydroxyl group at isobutyl C2 position [58,60]. Six alkamides, ZP-amide A (6), B (7), C (8), D (9), E (10) and F (11) with unsaturated fatty acid amides with hydroxyl and carbonyl substitutions were purified from the pericarp of Z. piperitum fruits, and, among these, 8 and 9 were racemic mixtures owing to optical inactivity. The relative configuration of 8 and 9 at C-10 and C-11 remains to be analyzed, while 11 is the stereoisomer of 10 with the relative configuration at the two asymmetric carbons, C-6 and C-11, 10 and 11 also being racemic mixtures owing to optical inactivity. The relative configuration and optical inactivity results of 8–11 were determined by 1D and 2D NMR and optical rotation [52]. Hydroxy-ζ-sanshool (12) was isolated from supercritical fluid extract in MeOH through MPLC and reversed-phase HPLC, where the two cis-configuration of double bonds in 12 was confirmed by expected cis-shielding effect of carbon atoms C-7 and C-14; finally, the trans-configuration of the double bond in 12 was detected by coupling constant of the two double duplets detected for H-10 and H-11 [61].

2.2.2. Alkamides from Zanthoxylum bungeanum

The CHCl3 extract of Z. bungeanum was chromatographed on a silica gel column and further isolated with reversed-phase HPLC to derive hydroxy-β-sanshool (13), (2E,4E,8E,10E,12E)-2′-Hydroxy-N-isobutyl-2,4,8,10,12-tetradecatetraenamide (named hydroxy-γ-isosanshool) (14) and (2E,4E,8Z,11Z)-N-(2-Hydroxy-2-methylpropyl)-2,4,8,11-tetradeeatetraenamide (named bungeanool) (15). These three alkamides contained a hydroxyl substitution at isobutyl C2 position [62]. A double-bond moiety linking to NH through a methylene group named dehydro-γ-sanshool (16) was isolated from an EtOH extract of dried pericarps of Z. bungeanum, while tetrahydrobungeanool (17), dihydrobungeanool (18) and isobungeanool (19) were also isolated from an EtOH extract of dried pericarps of Z. bungeanum [63]. (2E,7E,9E)-N-(2-hydroxy-2-methylpropyl)-6,11-dioxo-2,7,9-dodecatrienamide (20) containing two ketones located on an unsaturated carbon chain was isolated from a MeOH extract of pericarps of Z. bungeanum. In particular, (2E,6E,8E)-N-(2-Hydroxy-2-methylpropyl)-10-oxo-2,6,8-decatrienamide (21) containing a terminal aldehyde group on the unsaturated side chain was also isolated from the same extract [64].
Recent studies indicate that some alkamides have been successfully isolated from an EtOH/water plant extract. The pericarps of Z. bungeanum underwent treatment via 70% EtOH that was purified with a Sephadex LH-20 and preparative reversed-phase HPLC system to produce qinbunamide A–C (22–24), where 22 and 23 contained an ethoxy moiety attached on C-6 and C-11, respectively, while 24 contained carbonyl and hydroxyl groups on C-6 and C-11, respectively. Olefinic, carbonyl, hydroxyl and ethoxy groups in positions 22–24 were determined by 2D NMR; however, the stereochemistry of the ethoxy and hydroxyl moiety of 22–24 was still evidenced as a relative configuration [53]. A series of isobutylhydroxyamides 25–32 containing unsaturated carbon chains with carbonyl and hydroxyl groups were isolated from a 95% ethanol extract of the pericarp of Z. bungeanum [56].
In this study, 6 and 7, as obtained in a previous study [52], were separated by chiral columns to obtain enantiomers 6a/6b and enantiomers 7a/7b, respectively. The absolute configuration of enantiomeric 6a and 7a were determined as 6R and 11R, respectively; therefore, 6b and 7b were determined to be 6S and 11S, as they are the enantiomers of 6a and 7a. Compound 30 was a stereoisomer of 29 with different relative configurations at C-6 and C-7; 29 and 30 were also confirmed as erythro and threo forms, respectively. The relative configuration of 32 was the erythro form due to the coupling constant between H-6 and H-7 being the same as 29 [56]. Zanthoamide A (33), B (34), C (35) and D (36) and bugeanumamide A (37) were isolated from a 95% EtOH extract of powdered pericarps of Z. bungeanum. In addition, 33–35 also exhibited an unsaturated carbon chain substituted by carbonyl and hydroxyl groups. These four alkamides were racemic mixtures on account of the optical inactivity of these compounds. Compound 37 contained a rare C-6 fatty acid with an acetal group confirmed by 2D NMR correlation of OCH3 with H-6 and six protons of the two methoxyl groups as a strong singlet in 1H NMR [65].

2.2.3. Alkamides from Zanthoxylum lemairie (De Wild.)

Two aromatic alkamides, 38 and 39, were isolated from a CHCI3 extract of pericarps of Z. lemairie, revealing that the aromatic moiety was linked to the methoxy groups. Compared with the spectroscopic data of 38 and 39, the NMR absorption of N-CH3 on 39 confirmed that 39 is the N-methyl derivative of 38 [66].

2.2.4. Alkamides from Zanthoxylum Integrifoliolum (Merr.) Merr

Lanyuamides I–III (40–42) were isolated from a MeOH extract of fruits of Z. Integrifoliolum. The carbonylation on C-8 and C-12 of 40 and 41, respectively, were determined by the difference of the 1H NMR spectrum of methylene groups neighboring the keto group [67].

2.2.5. Alkamides from Zanthoxylum ailanthoides (Sieb. et Zucc.)

γ-sanshool (43) and hydroxy-γ-sanshool (44) were isolated from a MeOH extract of Z. ailanthoides. In the 13C NMR spectrum of 44, the carbon signal attached to hydroxyl moiety was shifted downfield in comparison with that of 43 and singlet in the off-resonance 13C NMR spectrum [68]. (2E,4E)-N-isobutyl-6-oxohepta-2,4-dienamide (45) was isolated from a MeOH extract of the stem bark of Z. ailanthoides through being chromatographed on silica gel and preparative TLC. The terminal acetyl group of the fatty acid of 45 was elucidated by 1D and 2D NMR correlation of C-4 to C-7 [69].

2.2.6. Alkamides from Zanthoxylum armatum DC

Dried pericarps of Z. armatum were extracted in MeOH to educe four alkamides, timuramides A–D (46–49), which were purified with diol batch elution, LH-20 Sephadex chromatography and C18-HPLC. In order to confirm absolute configuration of the endoperoxide ring of 46, it was converted into a secondary diol (46a) by hydrogenolysis of the peroxide with Lindlar’s catalyst [70]. The 1D NMR of 47 was like 46, except that it contained a C-6/C-7 trans-olefinic bond in contrast to the cis-configured bond in 46. The 1D NMR of 48 was similar to 46 and 47, except that it lacked an endoperoxide moiety and a terminal carboxylic acid at C-10 of 48. The 1D NMR of 49 was similar to 48, except that it lacked both C-6/C-7 and C-8/C-9 pairs of olefinic carbons [71].

2.2.7. Alkamides from Zanthoxylum nitidum (Roxb.) DC

Four unsaturated alkylamides, Zanthoxylum amides A–D (50–53), were purified from a 60% EtOH extract of the roots of Z. nitidum, using silica gel column CC by gradient elution and semi-preparative HPLC. The absolute configuration of hydroxylation and carbonylation carbons on the unsaturated structure of 50–53 could not be established due to the small amount of residue [72]. Zanthoxylum amides J–P (54–60) were isolated from the whole plant of Z. nitidum, extracted with 95% EtOH. The purification process included silica gel column CC and a Sephadex LH-20 column followed by reversed-phase HPLC. Compounds 54–60 exhibited hydroxyl, ethoxyl and carbonyl substitutions at an unsaturated carbon chain. The final configurations of racemic mixtures including 54 and 57–60 were determined by ECD [73]. (2E,6E,8E)-N-(2-methylpropyl)-10-oxo-2,6,8-decatrienamide (61) was isolated from the stems of Z. nitidum extracted with CH2Cl2. The unsaturated alkylamide of 61 possessing an aldehyde group was determined by 1D and 2D NMR spectrum, including the 2D NMR correlations between olefinic protons and aldehyde carbonyl carbon [74].

2.2.8. Alkamides from Zanthoxylum nitidum var. Tomentosum

From the dried whole herb of Z. nitidum, Zanthoxylum amides E–I (62–66) were purified by chromatography over silica gel, a Sephadex LH-20 column (MeOH) and semipreparative HPLC. The absolute configurations of the hydroxyl and methoxyl carbons of chiral racemic isobutylamides 62–65 were determined by ECD and 1D and 2D NMR, while the positions of enol moieties on the unsaturated structure of 62–66 were also confirmed by NMR spectrum [75].

2.2.9. Alkamides from Zanthoxylum heitzii

Pellitorine (67) and 6-hydroxypellitorine (68) were isolated from the bark of Z. heitzii extracted with hexane in a Soxhlet. The purification process was through the CH2Cl2/EtOAc system by silica gel column CC [76]. Compound 67 contained a secondary amide with an α,β-unsaturated conjugated system [77], while 68 was the derivative of C-6 hydroxylation of the unsaturated structure [78].

2.2.10. Alkamides from Zanthoxylum zanthoxyloides

Zanthoamides G (69) and I (70) were isolated from the fruits of Z. zanthoxyloides by reversed-phase preparative HPLC. Compounds 69 and 70 showed the hydroxylation of C-13, and 69 was a racemic mixture containing dihydroxyl moieties on C-12 and C-13, with a ketone carbonyl moiety being present on C-8 of 70 [79].

2.2.11. Alkamides from Zanthoxylum chalybeum

4-(isoprenyloxy)-3-methoxy-3,4-deoxymethylenedioxyfagaramide (71) was isolated from the ground stem bark of Z. chalybeum and extracted with sufficient volumes of 50% MeOH in CH2Cl2, containing an aromatic moiety attached to isoprenyloxy and methoxy groups [80].

3. Pharmacology: Local Anesthetic and Analgesic Effect

A local anesthetic provides its analgesic effect by inhibiting pain transmit pathways via a blockade of type A delta or C nerve impulses on sensory nerves [81]. The main anesthetic activities in the nervous system act on voltage-gated sodium channels (Nav), which are blocked and modulated to prevent conduction, thereby inhibiting sensory nerves’ communication [82]. To evaluate the main constituents of herbs possessing the ability to blockade sensory nerve transmission, the local anesthetic characteristics should be carefully identified. Sometimes, local analgesic properties may be mistaken to show local anesthetic effect but present a dysfunctional sensory nerve through the inhibition of transient receptor potential (TRP) channels [83]. The extracts from Z. species have been demonstrated to modulate sensory functions, such as suppressing pain [8,9]. Therefore, the Z. species’ pharmacological properties may have the potential to identify its main constituents closely associated with local anesthetic effects.
In this section, alkamides extracted from Z. species possessed pharmacological properties ranging from pungent and tingling sensations to analgesic and to local anesthetic effects (Table 1). In relation to alkamides’ regulation of main bioactivities and drug development perspectives, the structure–activity relationship of alkamides for their pharmacologic properties is also explored in further detail.

3.1. Pungent and Tingling Properties

Alkamides exhibiting pungent and tingling properties have been reported in species of Z. of the Rutaceae family. Compounds 2 and 5 produce similar tingling sensations when applied to the human tongue. Compound 2 has been observed to induce numbness during toothache treatment. In tests for spontaneous activity of the sensory system, compound 2 caused insensitivity to innocuous thermal or tactile stimuli as well as insensitivity to touch or cooling [85]. In a sensory functional evaluation of the alkamides 1–4, 13 and 43 from Z. bungeanum, compound 1 exhibited burning and tingling qualities and lasted the longest period in terms of stimulus duration among all sanshool compounds. Compound 3 was perceived as numbing and bitter, compound 4 as burning, numbing and fresh, compound 43 as burning and fresh, compound 2 as tingling and numbing, and compound 13 as numbing, astringent and bitter [84]. In the study reported by Bader et al., the sensory assay for evaluating pungent and/or tingling sensations showed that sanshool derivatives containing a Z-configuration double bond such as 2, 5, 15, 19 and 44, exhibited a tingling and paresthetic sensation; however, derivatives with an all-E configuration, specifically 13 and 14, induced numbing and anesthetic effects [53]. Compound 67, which is also an all-E configured alkamide, produces a numbing sensation on the tongue at a concentration of 10 ppm [90].

3.2. Analgesic Effect

The sensation is modulated by some key factors reported in previous studies. Transient receptor potential (TRP) channels are responsible for the sensations, which are thought to mediate pain and respond to natural compounds [91]. Compound 2 promoted Ca+2 influx in cells transfected with TRPV1 or TRPA1 and evoked robust inward currents in dorsal root ganglia neurons and trigeminal ganglion neurons transfected with TRPV1 or TRPA1 [86]. Compound 43 was a potent agonist of TRPV1 activity, which explains its pungent and tingling sensation, as well as its use as a natural anesthetic for toothache [84]. In electrophysiological experiments using Xenopus oocytes expressing compound 2, sensory neurons were excited through the inhibition of pH- and anesthetic-sensitive two-pore potassium channels (KCNK3, KCNK9 and KCNK18). Activation of TRPA1 and TRPV1 channels is mediated by sanshool alkamide 2, which blocks outward K+ current by activating KCNK channels. These channels are also targeted by volatile anesthetics, supporting the traditional use of Z. species extracts in folk medicine for treating toothache [87]. In behavioral assays, fiber recordings, calcium imaging and whole-cell electrophysiology of cultured sensory neurons, compound 2 inhibited the activity of multiple voltage-gated sodium channel subtypes, with Nav1.7 being the most strongly affected. It also inhibited Aδ mechanonociceptors, which mediate both sharp acute pain and inflammatory pain [88].

3.3. Local Anesthetic Effect

In the formalin test used to evaluate anesthetic effects, nanostructured lipid carriers loaded with compound 2 exhibited a significant anesthetic effect at a low dose compared to free compound 2 and the positive control lidocaine. Alkamides like compound 2 demonstrated potential for local analgesic effects. Regarding the duration of local anesthesia, formulation with compound 2 resulted in rapid onset and a sustained longer effect [89]. Until now, there have been few studies investigating the local anesthetic effects of pure alkamides, including in vivo and behavioral assays. Li et al. reported that water extracts from different processed products (high and low dosage groups) of Z. bungeanum exhibited a local anesthetic effect on the isolated sciatic nerve of rats [92]. In the Ma et al. report, water extract of Z. bungeanum exhibited higher alkamide contents compared to other solvent systems [51], indicating that some alkamides in the extract with local anesthetic effect are still unknown. In particular, plant extracts that are rich in alkamides are used in treatment as anesthetics in folk medicine [40]. It is necessary to determine the known or unknown alkamides isolated from plants and to further identify their local anesthetic effects.
This section explores the inference process from sensory properties such as numbing, modulation by key proteins including the TRP and KCNK series, and modulation factors for analgesic effects as determined from local anesthetic effects observed in assays. The above results indicate that alkamides have potential in the development of local anesthesia.

3.4. Structure–Activity Relationship for Pharmacology

Alkamides contain acyl chains with E/Z configurations double bonds. According to the sensory properties reported by Sugai et al., sanshool alkamides containing 2E and 6Z-double bonds in the acyl chain exhibited tingling sensations, similar to compounds 1 and 2. Alkamides with 2E- and 4E-double bonds in the acyl chain, such as compounds 4 and 43, were perceived as having a fresh sensation [84]. The stimulus duration assay indicated sanshool alkamides containing a Z-double bond, like 1, 2 and 43, exhibited longer stimulus than all-E isomers like 3, 4 and 13. Compound 1 also lasted the longest time in the measurement for duration of the stimulus [84]. It appears that 2E and 6Z-double bonds in the acyl chain are necessary for tingling intensity; furthermore, the Z-double bond in the acyl chain seems to be a critical element for sensory properties. According to the report by Bader et al. on the perception of pungency in hydroxy sanshool derivatives, compounds 2, 5, 15, 19 and 44 containing the Z-configuration exhibited a tingling sensation. In contrast, compounds 13 and 14 containing the all-E configuration exhibited a numbing and anesthetic sensation [61]. However, Sugai et al. reported in 2005 that compounds 1, 2 and 43 containing a Z-double bond also exhibited a numbing sensation [85].
As previously mentioned, the E/Z configuration possesses pungent and tingling properties. Other properties, like carbon chain length, hydroxylation on an isopropyl group and pattern of unsaturation, are also involved in sensory-active recognition. In the previous study, Galopin and Furrer tried to synthesize various sanshool alkamides and then explore the relationship between the structural composition of the numbing substances, with the numbing generation of proposed structural requirements shown in Figure 5. The minimal requirement for pungent intensity was R = H, n = 1, x = 1, and no conjugated Z-double bond existed in the structure. The additional optional feature could generate an obvious numbing sensation, i.e., two of the three conditions of the optional feature (R = OH, n = 2, x > 2) replacing the minimal requirements are sufficient to generate obvious numbing [93]. However, when the R group is replaced with -OH, as seen in compounds 2, 5, 15, 19 and 44, they exhibit tingling and paresthetic sensations, rather than numbing. [53]. On the other hand, sensory evaluations of a series of diols alkamides, including 8 and 9 from Z. piperitum and 54 and 65 from Z. nitidum, are still unknown. According to the hypothesis of structure in the Galopin and Furrer report (Figure 5), the structure of 65 may generate numbing sensation (R = H, n = 1, x > 2), while compounds 8, 9 and 54, which possess two optional features (8 and 9: R = OH, n = 1, x > 2; 54: R = H, n = 2, x > 2) might generate a more pronounced numbing sensation compared to compound 65 [52,75,93]. Compound 28 with an enol, 45 with an endoperoxide ring and 48 with a carboxylic acid moiety could also induce a more obvious numbing sensation (28: R = OH, n = 2, x > 2; 45 and 48: R = OH, n = 1, x > 2) [52,69,93]; however, the relationship between an oxygenated unsaturated carbon chain and the numbing sensation remains unclear. Accordingly, the pungent properties, including the numbing sensation of alkamides with oxygenated unsaturated carbon chains, should be further evaluated.
Previous studies have demonstrated that the Z configurations for double bond on the aryl chain of sanshool alkamides was an essential property for TRPV1 channel activation. A series of synthetic alkamides containing the modification of the unsaturated alkyl moiety from the Z-olefins structure was crucial in the activation of TRPA1 receptors [94], indicating that the 5Z or 6Z position of the double bond of alkamides is necessary for activating the TRPA1 channel (Figure 5), although the evaluation of TRPA1 and TRPV1 activities has only focused on compound 2 and its synthetic derivatives. To accurately confirm the active structure, more alkamide derivatives similar to compound 2 should be evaluated for their activities on TRPA1 and TRPV1 channels. In the Koo et al. report, compound 2 with 6Z-double bond activated TRPA1 and TRPV1 by evoking Ca2+ influx in cells, while, in the small sensory neurons, TRPV1 and TRPA1 were expressed primarily to mediate pain [86]. According to the hypothesis that the 6Z-double bond configuration in compound 2 is necessary for the activation of the TRPV1 and TRPA1 channel, a series of analogs such as compounds 5, 8, 9, 45, 48 and 65 also containing the 6Z-double bond might activate TRPV1 and TRPA1 to regulate pain.
The pharmacological study of alkamides has only focused on compound 2 for its local anesthetic effect, although the water extract of Z. bungeanum exhibited a significant local anesthetic effect on the isolated sciatic nerve of rats [92], where the compounds 8 and 9 were major alkamides found in the water extract of this variant. These two alkamides possess a 6Z-double bond and a hydroxyl group on the isopropyl moiety [51]. According to the Galopin and Furrer report, the structures of 8 and 9 could generate a more obvious numbing sensation (Figure 5) [52,93]. This biological property is related to the local anesthetic effect. The above results indicate that 8 and 9 might be the key constituents for the local anesthetic effect, and these two alkamides have the potential to be evaluated for their local anesthetic effect through detailed activity screening and extensive animal studies.

4. Pharmacokinetics

The pharmaceutical-grade traditional Japanese medicine, daikenchuto (TJ-100), was investigated in healthy Japanese volunteers after a single oral administration. Compound 2 as an ingredient in TJ-100 reached its maximum plasma concentration within 30 min after administration, with a median half-life of 1.6 to 1.7 h. The maximum plasma concentration of 2 ranged from 0.76 to 2.66 µM [95].
The chromatography method has also been applied for pharmacokinetic study effectively. A sensitive UHPLC–MS/MS method was developed and validated for determination of alkamides 2, 13 and 44 in rat plasma after subcutaneous and intravenous injections of Z. bungeanum EtOH extract. The results of plasma concentration indicated that 2, 13 and 44 were rapidly absorbed after subcutaneous administration, and all achieved a Cmax within 1 h, with the elimination half-life (t1/2) of these three alkamides being no more than 2.5 h. The subcutaneous absolute bioavailability of 2, 13 and 44 were 100.2, 76.2 and 90.3%, respectively. These results indicate that 2 was wider and more rapidly distributed in the plasma compared with 13 and 44 due to its all-trans polyene structure with a lower polarity and a higher oil distribution coefficient [96].
The pharmacokinetic analysis of compound 38 in the brain showed that it could be absorbed into the blood and rapidly cross specialized barriers like the blood–brain barrier (BBB) after oral administration. It is metabolized in the liver and excreted via the kidneys. Compound 38 was quickly distributed to brain tissue (within 5 min post oral administration) and was finally excreted approximately 4 h post oral administration [97]. The lipid-soluble structure of alkamides enhances their permeability through the blood–brain barrier (BBB). Current studies have indicated that alkamides from Z. species exhibit favorable absorption, elimination in the bloodstream and penetration into brain tissue, although these studies have primarily focused on a limited number of alkamides such as 2 and 38, highlighting the need for more comprehensive pharmacokinetic analyses across various types of alkamide.
Drug metabolism is also a crucial aspect of pharmacokinetics, influencing predictions of drug efficacy, safety and toxicity. Sanshool-type alkamides, such as compound 2, are the main active components in Z. bungeanum and have been the focus of drug metabolism research. A recent study indicated that the metabolic stability of 2 in human and rat liver microsomes, as well as human hepatocytes, was superior to that in monkeys, dogs and mice. Compound 2 also demonstrated strong inhibitory effects on CYP2C9 and CYP2D6 in human liver microsomes [98]. In Z. species, alkamides exhibit metabolic stability and strong non-specific binding to plasma proteins, although the detailed molecular mechanisms, including protein-catalyzed metabolite production, remain unclear. Previous studies have indicated that the synthetic isobutylamide (2E,4E,8Z,10Z)-N-isobutyldodeca-2,4,8,10-tetraenamide undergoes epoxidation at double bonds catalyzed by microsomal cytochrome P450 enzymes. Metabolites of synthetic isobutylamide detected by LC-MS showed an apparent molecular weight of 263 amu, suggesting simple epoxidation or hydroxylation [99]. Subsequent studies have revealed that different forms of P450 exhibit specific catalytic reactions. Two isoforms, CYP1A1 and CYP1A2, produced identical epoxide and N-dealkylation products, while, in contrast, CYP2D6 generated two distinct epoxides and a hydroxylated metabolite [100]. The above studies infer a relationship with the metabolism of alkamides in Z. species, allowing for predictions on how enzymes catalyze the formation of epoxidation or hydroxylation metabolites. According to this inference, the Z form double bonds in the structure are most likely epoxidated or hydroxylated by P450.

5. Clinical Application

The pharmacokinetic study of the alkamides of plants allows the prediction of clinical usage. In human volunteers, the plasma concentration results of two alkamides in the traditional Japanese medicine TJ-100, including the maximum plasma concentration after administration and the elimination half-life, provide crucial information for their clinical application. These results also indicate how to carefully control the administration range to prevent excessive absorption and the potential danger of side effects [95]. In the Rong er al. report, the pharmacokinetic study of the alkamides of Z. bungeanum EtOH extract, including plasma concentration, elimination half-life and subcutaneous absolute bioavailability, provides valuable information for improving the prediction of clinical outcomes. The pharmacokinetic behaviors of 2, 13 and 44 in Z. bungeanum EtOH extract were used for the clinical application of anesthetics. To prevent potential side effects and ensure better clinical application, the dosage of compound 2 was carefully and accurately controlled due to its high subcutaneous bioavailability [96].
The formalin test is utilized in preclinical pain research to elucidate the action mechanisms and analgesic effects of novel compounds, particularly those related to their local anesthetic effects [97]. Nociceptive behavior triggered in the formalin test consists of two phases: in phase I, the nociceptors are activated by formalin acutely through non-nociceptive Aβ fibers; in phase II, the activity is driven partly by central sensitization of spinal cord circuits [101]. In electrophysiological studies, Aδ- and C-fiber nociceptors exhibit activity during both phases of the formalin test [102], and, in this test, compound 2 combined with nanostructured lipid carriers revealed remarkable pain-relieving effects at various phases of the formalin test compared to the control group and lidocaine. Compound 2 probably could inhibit nociceptors (such as C-fiber, Aβ-fiber and Aδ-fiber) in the somatosensory neurons through blocking various Nav channel subtypes to reduce pain behavior [89]; accordingly, compound 2 might serve as a potential local anesthetic in clinical applications.

6. Conclusions and Perspectives

Alkamides that are present and enriched in numerous Z. species of plants are recognized for their pain-suppressing properties and their potential in the development of local anesthetic research. Various traditional medical practices involving these plants have shown beneficial effects in pain modulation globally. Current phytochemical studies indicate that alkamides exhibit specific stereochemical characteristics due to isomerization of their configurations, often existing as racemic mixtures in plants despite their relatively simple and similar structures; consequently, the detection, isolation and elucidation of a series of alkamides using various chromatographic and spectroscopic methods are crucial for confirming the constituents present in these plants.
The research on pungent, tingling and numbing sensations, as well as the analgesic effects of alkamides, is crucial for understanding their local anesthetic properties. These properties are intricately linked to their structural characteristics and are essential considerations in drug design, although current studies on local anesthetic effects and related bioactivities of alkamides are limited, particularly regarding specific compounds, and few studies have deeply investigated the mechanisms underlying their local anesthetic effects and related analgesic properties. Thus, key questions remain that need to be answered in future research:
(a)
Until now, the efficacy of compound 2 has been demonstrated in relatively complete studies, including its pungent and tingling properties, the mechanism of analgesic effect and the local anesthetic effect; however, no other alkamide has been identified with similarly detailed molecular mechanisms for these effects and properties, and a series of alkamides similar to 2 should be further investigated accordingly. The examination of alkamides for local anesthetic effect and related bioactive properties should be wide-ranging and not merely focused on specific compounds.
(b)
The studies on alkamides should not be limited to phytochemistry and primary in vitro assays but should encompass a full series of investigations of their pharmacological effects.
(c)
The SARs of alkamides related to their pungent, tingling, analgesic and local anesthetic effects have been hypothesized and remain largely theoretical, requiring detailed investigations to confirm these relationships.
(d)
The results of pharmacokinetic studies are pivotal for clinical applications, as they furnish essential references for subsequent clinical research. Despite this significance, only a limited number of alkamides or crude extracts enriched with alkamides have been directly tested in clinical trials. It is therefore crucial to emphasize the need for a broader exploration and evaluation methodology of various types of alkamides through clinical testing, which is essential to substantiate their safety and efficacy profiles, thereby facilitating their correspondently safe and effective use in clinical settings.
In future studies, it is imperative to deepen research on alkamides or plants containing alkamides, focusing on the issues outlined above, to advance the development of local anesthesia from natural sources. This review aims to consolidate the current studies on phytochemistry and pharmacology related to local anesthetic effects and other activities, pharmacokinetics and clinical applications of alkamides derived from Z. species. Such an approach could accelerate the development of natural, plant-derived local anesthetics from Z. species that could potentially offer safer and more effective alternatives to their synthetic counterparts.

Author Contributions

I.-C.L., L.-L.C., H.-C.W. and K.-I.C.: Revised and supervised the manuscript. P.-Y.H. and C.-H.L.: Formal analysis. T.-P.G. and K.-W.L.: Designed, coordinated the data and information, and drafted and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Asase, A.; Oppong-Mensah, G. Traditional antimalarial phytotherapy remedies in herbal markets in southern Ghana. J. Ethnopharmacol. 2009, 126, 492–499. [Google Scholar] [CrossRef] [PubMed]
  2. Phuyal, N.; Jha, P.K.; Prasad Raturi, P.; Rajbhandary, S. Zanthoxylum armatum DC.: Current knowledge, gaps and opportunities in Nepal. J. Ethnopharmacol. 2019, 229, 326–341. [Google Scholar] [CrossRef] [PubMed]
  3. Plazas, E.; Casoti, R.; Avila Murillo, M.; Batista Da Costa, F.; Cuca, L.E. Metabolomic profiling of Zanthoxylum species: Identification of anti-cholinesterase alkaloids candidates. Phytochemistry 2019, 168, 112128. [Google Scholar] [CrossRef] [PubMed]
  4. Okagu, I.U.; Ndefo, J.C.; Aham, E.C.; Udenigwe, C.C. Zanthoxylum species: A comprehensive review of traditional uses, phytochemistry, pharmacological and nutraceutical applications. Molecules 2021, 26, 4023. [Google Scholar] [CrossRef] [PubMed]
  5. Mutinda, E.S.; Kimutai, F.; Mkala, E.M.; Waswa, E.N.; Odago, W.O.; Nanjala, C.; Ndungu, C.N.; Gichua, M.K.; Njire, M.M.; Gituru, R.W.; et al. Ethnobotanical uses, phytochemistry and pharmacology of pantropical genus Zanthoxylum L. (Rutaceae): An update. J. Ethnopharmacol. 2023, 303, 115895. [Google Scholar] [CrossRef]
  6. Qin, F.; Zhang, H.; Liu, A.; Wang, Q.; Sun, Q.; Lu, S.; Li, Q.; Guo, H.; Liu, X.; Lu, Z. Analgesic Effect of Zanthoxylum nitidum extract in inflammatory pain models through targeting of ERK and NF-κB signaling. Front. Pharmacol. 2019, 10, 359. [Google Scholar] [CrossRef]
  7. Wang, Y.; Yang, S.H.; Zhong, K.; Jiang, T.; Zhang, M.; Kwan, H.Y.; Su, T. Network pharmacology-based strategy for the investigation of the anti-obesity effects of an ethanolic extract of Zanthoxylum bungeanum Maxim. Front. Pharmacol. 2020, 11, 572387. [Google Scholar] [CrossRef]
  8. Huang, Y.; Gong, Z.; Yan, C.; Zheng, K.; Zhang, L.; Li, J.; Liang, E.; Zhang, L.; Mao, J. Investigation on the mechanisms of Zanthoxylum bungeanum for treating diabetes mellitus based on network pharmacology, molecular docking, and experiment verification. Biomed. Res. Int. 2023, 2023, 9298728. [Google Scholar] [CrossRef]
  9. Lu, Q.; Ma, R.; Yang, Y.; Mo, Z.; Pu, X.; Li, C. Zanthoxylum nitidum (Roxb.) DC: Traditional uses, phytochemistry, pharmacological activities and toxicology. J. Ethnopharmacol. 2020, 260, 112946. [Google Scholar] [CrossRef]
  10. Enechi, O.C.; Amah, C.C.; Okagu, I.U.; Ononiwu, C.P.; Azidiegwu, V.C.; Ugwuoke, E.O.; Onoh, A.P.; Ndukwe, E.E. Methanol extracts of Fagara zanthoxyloides leaves possess antimalarial effects and normalizes haematological and biochemical status of Plasmodium berghei-passaged mice. Pharm. Biol. 2019, 57, 577–585. [Google Scholar] [CrossRef]
  11. Andima, M.; Coghi, P.; Yang, L.J.; Wong, V.K.W.; Ngule, C.M.; Heydenreich, M.; Ndakala, A.J.; Yenesew, A.; Derese, S. Antiproliferative activity of secondary metabolites from Zanthoxylum zanthoxyloides Lam: In vitro and in silico studies. Pharmacogn. Commun. 2020, 10, 44–51. [Google Scholar] [CrossRef]
  12. Nuto, Y. Characteristics, fatty acid profile, strategic importance of Zanthoxylum zanthoxyloides (rutaceae) seed oil and sustainable conservation of the species. Int. J. Dev. 2018, 8, 21425–21429. [Google Scholar]
  13. Nwankwo, O.S.; Chioma, C.G.; Ofem, O.W.; Amara, E.M.; Chijioke, M.C. Aqueous methanol extract of the root bark of Zanthoxylum zanthoxyloides provides natural remedy for dental caries and toothache. World J. Pharm. Res. 2017, 6, 336–349. [Google Scholar] [CrossRef]
  14. Cui, H.Z.; Choi, H.R.; Choi, D.H.; Cho, K.W.; Kang, D.G.; Lee, H.S. Aqueous extract of Zanthoxylum schinifolium elicits contractile and secretory responses via beta1-adrenoceptor activation in beating rabbit atria. J. Ethnopharmacol. 2009, 126, 300–307. [Google Scholar] [CrossRef]
  15. Diéguez-Hurtado, R.; Garrido-Garrido, G.; Prieto-González, S.; Iznaga, Y.; González, L.; Molina-Torres, J.; Curini, M.; Epifano, F.; Marcotullio, M.C. Antifungal activity of some Cuban Zanthoxylum species. Fitoterapia 2003, 74, 384–386. [Google Scholar] [CrossRef]
  16. Dos, S.B.P.J.; Torquato, H.F.; Dos Santos, C.H.; Carvalho, M.G.; Castro, R.N.; Paredes-Gamero, E.J.; de Sousa, P.T., Jr.; Jacinto, M.J.; da Silva, V.C. [1-8-NαC]-Zanriorb A1, a proapoptotic orbitide from leaves of Zanthoxylum riedelianum. J. Nat. Prod. 2016, 79, 1454–1458. [Google Scholar] [CrossRef]
  17. Bafi-Yeboa, N.F.; Arnason, J.T.; Baker, J.; Smith, M.L. Antifungal constituents of northern prickly ash, Zanthoxylum americanum mill. Phytomedicine 2005, 12, 370–377. [Google Scholar] [CrossRef]
  18. Gong, Y.; Huang, Y.; Zhou, L.; Shi, X.; Guo, Z.; Wang, M.; Jiang, W. Chemical composition and antifungal activity of the fruit oil of Zanthoxylum bungeanum Maxim. (Rutaceae) from China. J. Essent. Oil Res. 2009, 21, 174–178. [Google Scholar] [CrossRef]
  19. Ross, S.A.; Sultana, G.N.; Burandt, C.L.; ElSohly, M.A.; Marais, J.P.; Ferreira, D. Syncarpamide, a new antiplasmodial (+)-norepinephrine derivative from Zanthoxylum syncarpum. J. Nat. Prod. 2004, 67, 88–90. [Google Scholar] [CrossRef]
  20. Matu, E.N.; van Staden, J. Antibacterial and anti-inflammatory activities of some plants used for medicinal purposes in Kenya. J. Ethnopharmacol. 2003, 87, 35–41. [Google Scholar] [CrossRef]
  21. Jamir, K.; Seshagirirao, K.; Meitei, M.D. Indigenous oral knowledge of wild medicinal plants from the Peren district of Nagaland, India in the Indo Burma hot-spot. Acta Ecol. Sin. 2022, 42, 206–223. [Google Scholar] [CrossRef]
  22. Dzoyem, J.P.; Guru, S.K.; Pieme, C.A.; Kuete, V.; Sharma, A.; Khan, I.A.; Saxena, A.K.; Vishwakarma, R.A. Cytotoxic and antimicrobial activity of selected Cameroonian edible plants. BMC Complement. Altern. Med. 2013, 13, 78. [Google Scholar] [CrossRef] [PubMed]
  23. Greger, H. Alkamides: A critical reconsideration of a multifunctional class of unsaturated fatty acid amides. Phytochem. Rev. 2016, 15, 729–770. [Google Scholar] [CrossRef]
  24. Greger, H. Alkamides: Structural relationships, distribution and biological activity. Planta Med. 1984, 50, 366–375. [Google Scholar] [CrossRef]
  25. Chruma, J.J.; Cullen, D.J.; Bowman, L.; Toy, P.H. Polyunsaturated fatty acid amides from the Zanthoxylum genus—From culinary curiosities to probes for chemical biology. Nat. Prod. Rep. 2018, 35, 54–74. [Google Scholar] [CrossRef]
  26. Okagu, I.U.; Ndefo, J.C.; Aham, E.C.; Udenigwe, C.C. Zanthoxylum species: A review of traditional uses, phytochemistry and pharmacology in relation to cancer, infectious diseases and sickle cell anemia. Front. Pharmacol. 2021, 12, 713090. [Google Scholar] [CrossRef]
  27. Boonen, J.; Bronselaer, A.; Nielandt, J.; Veryser, L.; De Tré, G.; De Spiegeleer, B. Alkamid database: Chemistry, occurrence and functionality of plant N-alkylamides. J. Ethnopharmacol. 2012, 142, 563–590. [Google Scholar] [CrossRef]
  28. Molina-Torres, J.; García-Chávez, A.; Ramírez-Chávez, E. Antimicrobial properties of alkamides present in flavouring plants traditionally used in Mesoamerica: Affinin and capsaicin. J. Ethnopharmacol. 1999, 64, 241–248. [Google Scholar] [CrossRef]
  29. Dossou, K.S.; Devkota, K.P.; Morton, C.; Egan, J.M.; Lu, G.; Beutler, J.A.; Moaddel, R. Identification of CB1/CB2 ligands from Zanthoxylum bungeanum. J. Nat. Prod. 2013, 76, 2060–2064. [Google Scholar] [CrossRef]
  30. Ren, T.; Zhu, Y.; Xia, X.; Ding, Y.; Guo, J.; Kan, J. Zanthoxylum alkylamides ameliorate protein metabolism disorder in STZ-induced diabetic rats. J. Mol. Endocrinol. 2017, 58, 113–125. [Google Scholar] [CrossRef]
  31. Ku, S.K.; Lee, I.C.; Kim, J.A.; Bae, J.S. Anti-septic effects of pellitorine in HMGB1-induced inflammatory responses in vitro and in vivo. Inflammation 2014, 37, 338–348. [Google Scholar] [CrossRef] [PubMed]
  32. Hajdu, Z.; Nicolussi, S.; Rau, M.; Lorántfy, L.; Forgo, P.; Hohmann, J.; Csupor, D.; Gertsch, J. Identification of endocannabinoid system-modulating N-alkylamides from Heliopsis helianthoides var. scabra and Lepidium meyenii. J. Nat. Prod. 2014, 77, 1663–1669. [Google Scholar] [CrossRef] [PubMed]
  33. Dallazen, J.L.; Maria-Ferreira, D.; da Luz, B.B.; Nascimento, A.M.; Cipriani, T.R.; de Souza, L.M.; Glugoski, L.P.; Silva, B.J.G.; Geppetti, P.; de Paula Werner, M.F. Distinct mechanisms underlying local antinociceptive and pronociceptive effects of natural alkylamides from Acmella oleracea compared to synthetic isobutylalkyl amide. Fitoterapia 2018, 131, 225–235. [Google Scholar] [CrossRef] [PubMed]
  34. Liu, Y.; Yadev, V.R.; Aggarwal, B.B.; Nair, M.G. Inhibitory effects of black pepper (Piper nigrum) extracts and compounds on human tumor cell proliferation, cyclooxygenase enzymes, lipid peroxidation and nuclear transcription factor-kappa-B. Nat. Prod. Commun. 2010, 5, 1253–1257. [Google Scholar] [CrossRef]
  35. Cai, F.; Wang, C. Comprehensive review of the phytochemistry, pharmacology, pharmacokinetics, and toxicology of alkamides (2016–2022). Phytochemistry 2024, 220, 114006. [Google Scholar] [CrossRef]
  36. López, K.S.; Marques, A.M.; Moreira, D.L.; Velozo, L.S.; Sudo, R.T.; Zapata-Sudo, G.; Guimarães, E.F.; Kaplan, M.A. Local anesthetic activity from extracts, fractions and pure compounds from the roots of Ottonia anisum Spreng. (Piperaceae). An. Acad. Bras. Ciênc. 2016, 88, 2229–2237. [Google Scholar] [CrossRef]
  37. Luo, J.; Ke, J.; Hou, X.; Li, S.; Luo, Q.; Wu, H.; Shen, G.; Zhang, Z. Composition, structure and flavor mechanism of numbing substances in Chinese prickly ash in the genus Zanthoxylum: A review. Food Chem. 2022, 373 Pt B, 131454. [Google Scholar] [CrossRef]
  38. Elufioye, T.O.; Habtemariam, S.; Adejare, A. Chemistry and pharmacology of alkylamides from natural origin. Rev. Bras. Farmacogn. 2020, 30, 622–640. [Google Scholar] [CrossRef]
  39. Méndez-Bravo, A.; Calderón-Vázquez, C.; Ibarra-Laclette, E.; Raya-González, J.; Ramírez-Chávez, E.; Molina-Torres, J.; Guevara-García, A.A.; López-Bucio, J.; Herrera-Estrella, L. Alkamides activate jasmonic acid biosynthesis and signaling pathways and confer resistance to Botrytis cinerea in Arabidopsis thaliana. PLoS ONE 2011, 6, e27251. [Google Scholar] [CrossRef]
  40. Rios, M.Y. Natural alkamides: Pharmacology, chemistry and distribution. Nat. Rev. Drug Discov. 2012, 244, 107–144. [Google Scholar]
  41. Wang, R.; Rao, C.; Liu, Q.; Liu, X. Degradation and transformation mechanisms of Zanthoxylum Alkylamides exposed to UVB light. Foods 2023, 12, 4392. [Google Scholar] [CrossRef] [PubMed]
  42. Yang, X. Aroma constituents and alkylamides of red and green huajiao (Zanthoxylum bungeanum and Zanthoxylum schinifolium). J. Agric. Food Chem. 2008, 56, 1689–1696. [Google Scholar] [CrossRef] [PubMed]
  43. Liu, Y.; Murphy, P.A. Alkamide stability in Echinacea purpurea extracts with and without phenolic acids in dry films and in solution. J. Agric. Food Chem. 2007, 55, 120–126. [Google Scholar] [CrossRef] [PubMed]
  44. Molina-Torres, J.; Salazar-Cabrera, C.J.; Armenta-Salinas, C.; Ramírez-Chávez, E. Fungistatic and bacteriostatic activities of alkamides from Heliopsis longipes roots: Affinin and reduced amides. J. Agric. Food Chem. 2004, 52, 4700–4704. [Google Scholar] [CrossRef] [PubMed]
  45. Glazebrook, J. Genes controlling expression of defense responses in Arabidopsis—2001 status. Curr. Opin. Plant Biol. 2001, 4, 301–308. [Google Scholar] [CrossRef]
  46. Zhang, J.; Wu, Z.; Han, N.; Wang, D. Functional validation of ZbFAD2 and ZbFAD3 in the alkylamide biosynthesis pathway from Zanthoxylum bungeanum Maxim. Front. Plant Sci. 2022, 13, 991882. [Google Scholar] [CrossRef]
  47. López-Bucio, J.; Millán-Godínez, M.; Méndez-Bravo, A.; Morquecho-Contreras, A.; Ramírez-Chávez, E.; Molina-Torres, J.; Pérez-Torres, A.; Higuchi, M.; Kakimoto, T.; Herrera-Estrella, L. Cytokinin receptors are involved in alkamide regulation of root and shoot development in Arabidopsis. Plant Physiol. 2007, 145, 1703–1713. [Google Scholar] [CrossRef]
  48. Méndez-Bravo, A.; Raya-González, J.; Herrera-Estrella, L.; López-Bucio, J. Nitric oxide is involved in alkamide-induced lateral root development in Arabidopsis. Plant Cell Physiol. 2010, 51, 1612–1626. [Google Scholar] [CrossRef]
  49. Azwanida, N. A review on the extraction methods use in medicinal plants, principle, strength and limitation. Med. Aromat. Plants 2015, 4, 1000196. [Google Scholar]
  50. Abubakar, A.R.; Haque, M. Preparation of medicinal plants: Basic extraction and fractionation procedures for experimental purposes. J. Pharm. Bioallied Sci. 2020, 12, 1–10. [Google Scholar] [CrossRef]
  51. Ma, Y.; Wang, Y.; Li, X.; Hou, L.X.; Wei, A.Z. Sensory characteristics and antioxidant activity of Zanthoxylum bungeanum Maxim. pericarps. Chem. Biodivers. 2019, 16, e1800238. [Google Scholar] [CrossRef] [PubMed]
  52. Hatano, T.; Inada, K.; Ogawa, T.O.; Ito, H.; Yoshida, T. Aliphatic acid amides of the fruits of Zanthoxylum piperitum. Phytochemistry 2004, 65, 2599–2604. [Google Scholar] [CrossRef] [PubMed]
  53. Tian, J.M.; Wang, Y.; Xu, Y.Z.; Yu, Z.C.; Wei, A.Z.; Zhang, W.M.; Gao, J.M. Characterization of isobutylhydroxyamides with NGF-potentiating activity from Zanthoxylum bungeanum. Bioorg. Med. Chem. Lett. 2016, 26, 338–342. [Google Scholar] [CrossRef] [PubMed]
  54. Ahmad Dar, A.; Sangwan, P.L.; Kumar, A. Chromatography: An important tool for drug discovery. J. Sep. Sci. 2020, 43, 105–119. [Google Scholar] [CrossRef]
  55. Manayi, A.; Vazirian, M.; Saeidnia, S. Echinacea purpurea: Pharmacology, phytochemistry and analysis methods. Pharmacogn. Rev. 2015, 9, 63–72. [Google Scholar]
  56. Chen, J.; Zhang, T.; Zhang, Q.; Liu, Y.; Li, L.; Si, J.; Zou, Z.; Hua, H. Isobutylhydroxyamides from Sichuan pepper and their protective activity on PC12 cells damaged by corticosterone. J. Agric. Food Chem. 2018, 66, 3408–3416. [Google Scholar] [CrossRef]
  57. Crombie, L.; Tayler, J.L. 533. Amides of vegetable origin. Part VIII. The constitution and configuration of the sanshoöls. J. Chem. Soc. 1957, 2760–2766. [Google Scholar] [CrossRef]
  58. Yasuda, I.; Takeya, K.; Itokawa, H. Distribution of unsaturated aliphatic acid amides in Japanese Zanthoxylum species. Phytochemistry 1982, 21, 1295–1298. [Google Scholar] [CrossRef]
  59. Kashiwada, Y.; Ito, C.; Katagiri, H.; Mase, I.; Komatsu, K.; Namba, T.; Ikeshiro, Y. Amides of the fruit of Zanthoxylum spp. Phytochemistry 1997, 44, 1125–1127. [Google Scholar] [CrossRef]
  60. Jang, K.H.; Chang, Y.H.; Kim, D.D.; Oh, K.B.; Oh, U.; Shin, J. New polyunsaturated fatty acid amides isolated from the seeds of Zanthoxylum piperitum. Arch. Pharm. Res. 2008, 31, 569–572. [Google Scholar] [CrossRef]
  61. Bader, M.; Stark, T.D.; Dawid, C.; Lösch, S.; Hofmann, T. All-trans-configuration in Zanthoxylum alkylamides swaps the tingling with a numbing sensation and diminishes salivation. J. Agric. Food Chem. 2014, 62, 2479–2488. [Google Scholar] [CrossRef] [PubMed]
  62. Mizutani, K.; Fukunaga, Y.; Tanaka, O.; Takasugi, N.; Saruwatari, Y.I.; Fuwa, T.; Yamauchi, T.; Wang, J.; Jia, M.R.; Li, F.Y.; et al. Amides from huajiao, pericarps of Zanthoxylum bungeanum MAXIM. Chem. Pharm. Bull. 1988, 36, 2362–2365. [Google Scholar] [CrossRef]
  63. Xiong, Q.; Dawen, S.; Yamamoto, H.; Mizuno, M.J.P. Alkylamides from pericarps of Zanthoxylum bungeanum. Phytochemistry 1997, 46, 1123–1126. [Google Scholar] [CrossRef]
  64. Huang, S.; Zhao, L.; Zhou, X.L.; Ying, M.; Wang, C.J.; Weng, J. New alkylamides from pericarps of Zanthoxylum bungeanum. Chin. Chem. Lett. 2012, 23, 1247–1250. [Google Scholar] [CrossRef]
  65. Wang, Y.; Li, C.H.; Luo, B.; Sun, Y.N.; Kim, Y.H.; Wei, A.Z.; Gao, J.M. Isobutylhydroxyamides from Zanthoxylum bungeanum and their suppression of NO production. Molecules 2016, 21, 1416. [Google Scholar] [CrossRef]
  66. Adesina, S.K.; Olugbade, T.A.; Akinwusi, D.D.; von Willert, D.J. New amides from Zanthoxylum lemairie pericarps. Planta Med. 1997, 63, 286–287. [Google Scholar] [CrossRef]
  67. Chen, I.S.; Chen, T.L.; Lin, W.Y.; Tsai, I.L.; Chen, Y.C. Isobutylamides from the fruit of Zanthoxylum integrifoliolum. Phytochemistry 1999, 52, 357–360. [Google Scholar] [CrossRef]
  68. Yasuda, I.; Takeya, K.; Itokawa, H. Two new pungent principles isolated from the pericarps of Zanthoxylum ailanthoides. Chem. Pharm. Bull. 1981, 29, 1791–1793. [Google Scholar] [CrossRef]
  69. Chen, J.J.; Chung, C.Y.; Hwang, T.L.; Chen, J.F. Amides and benzenoids from Zanthoxylum ailanthoides with inhibitory activity on superoxide generation and elastase release by neutrophils. J. Nat. Prod. 2009, 72, 107–111. [Google Scholar] [CrossRef]
  70. Rostami, A.; Wang, Y.; Arif, A.M.; McDonald, R.; West, F.G. Intramolecular azide trapping of the Nazarov intermediate: Formation of peroxy-bridged indolizidinones via a deep-seated rearrangement and aerobic oxidation. Org. lett. 2007, 9, 703–706. [Google Scholar] [CrossRef]
  71. Devkota, K.P.; Wilson, J.; Henrich, C.J.; McMahon, J.B.; Reilly, K.M.; Beutler, J.A. Isobutylhydroxyamides from the pericarp of Nepalese Zanthoxylum armatum inhibit NF1-defective tumor cell line growth. J. Nat. Prod. 2013, 76, 59–63. [Google Scholar] [CrossRef] [PubMed]
  72. Zhu, L.J.; Ren, M.; Yang, T.C.; Qiao, C.; Chen, B.B.; Han, Z.Z.; Wang, S.H.; Wen, P.; Zhang, X. Four new alkylamides from the roots of Zanthoxylum nitidum. J. Asian Nat. Prod. Res. 2015, 17, 711–716. [Google Scholar] [CrossRef] [PubMed]
  73. Qin, F.; Wang, C.G.; Li, M.S.; Li, J.J.; Wei, G.; Liao, N.; Wang, H.S. Structurally diverse isobutylamides from Zanthoxylum nitidum. Fitoterapia 2023, 164, 105381. [Google Scholar] [CrossRef] [PubMed]
  74. Chakthong, S.; Ampaprom, R.; Inparn, S.; Phetkul, U.; Chusri, S.; Limsuwan, S.; Voravuthikunchai, S.P. New alkylamide from the stems of Zanthoxylum nitidum. Nat. Prod. Res. 2019, 33, 153–161. [Google Scholar] [CrossRef]
  75. Qin, F.; Wang, C.Y.; Hu, R.; Wang, C.G.; Wang, F.F.; Zhou, M.M.; Liang, D.; Liao, H.B.; Lee, S.K.; Wang, H.S. Anti-inflammatory activity of isobutylamides from Zanthoxylum nitidum var. tomentosum. Fitoterapia 2020, 142, 104486. [Google Scholar] [CrossRef]
  76. Wangensteen, H.; Ho, G.T.; Tadesse, M.; Miles, C.O.; Moussavi, N.; Mikolo, B.; Malterud, K.E. A new benzophenanthridine alkaloid and other bioactive constituents from the stem bark of Zanthoxylum heitzii. Fitoterapia 2016, 109, 196–200. [Google Scholar] [CrossRef]
  77. Rosario, S.L.; da Silva, A.J.; Parente, J.P. Alkamides from Cissampelos glaberrima. Planta Med. 1996, 62, 376–377. [Google Scholar] [CrossRef]
  78. Ahmed, A.; Aboul-Ela, M.; El-Din, A. New alkamide from Anacyclus monanthos. Pharmazie 1990, 45, 941–945. [Google Scholar]
  79. Guetchueng, S.T.; Nahar, L.; Ritchie, K.J.; Ismail, F.M.; Evans, A.R.; Sarker, S. Zanthoamides GI: Three new alkamides from Zanthoxylum zanthoxyloides. Phytochem. Lett. 2018, 26, 125–129. [Google Scholar] [CrossRef]
  80. Omosa, L.K.; Mbogo, G.M.; Korir, E.; Omole, R.; Seo, E.J.; Yenesew, A.; Heydenreich, M.; Midiwo, J.O.; Efferth, T. Cytotoxicity of fagaramide derivative and canthin-6-one from Zanthoxylum (Rutaceae) species against multidrug resistant leukemia cells. Nat. Prod. Res. 2021, 35, 579–586. [Google Scholar] [CrossRef]
  81. Vadhanan, P.; Tripaty, D.K.; Adinarayanan, S. Physiological and pharmacologic aspects of peripheral nerve blocks. J. Anaesthesiol. Clin. Pharmacol. 2015, 31, 384–393. [Google Scholar] [CrossRef] [PubMed]
  82. Sun, H.; Kollarik, M.; Undem, B.J. Blocking voltage-gated sodium channels as a strategy to suppress pathological cough. Pulm. Pharmacol. Ther. 2017, 47, 38–41. [Google Scholar] [CrossRef] [PubMed]
  83. Leffler, A.; Lattrell, A.; Kronewald, S.; Niedermirtl, F.; Nau, C. Activation of TRPA1 by membrane permeable local anesthetics. Mol. Pain. 2011, 7, 62. [Google Scholar] [CrossRef] [PubMed]
  84. Sugai, E.; Morimitsu, Y.; Iwasaki, Y.; Morita, A.; Watanabe, T.; Kubota, K. Pungent qualities of sanshool-related compounds evaluated by a sensory test and activation of rat TRPV1. Biosci. Biotechnol. Biochem. 2005, 69, 1951–1957. [Google Scholar] [CrossRef] [PubMed]
  85. Bryant, B.P.; Mezine, I. Alkylamides that produce tingling paresthesia activate tactile and thermal trigeminal neurons. Brain Res. 1999, 842, 452–460. [Google Scholar] [CrossRef]
  86. Koo, J.Y.; Jang, Y.; Cho, H.; Lee, C.H.; Jang, K.H.; Chang, Y.H.; Shin, J.; Oh, U. Hydroxy-alpha-sanshool activates TRPV1 and TRPA1 in sensory neurons. Eur. J. Neurosci. 2007, 26, 1139–1147. [Google Scholar] [CrossRef]
  87. Bautista, D.M.; Sigal, Y.M.; Milstein, A.D.; Garrison, J.L.; Zorn, J.A.; Tsuruda, P.R.; Nicoll, R.A.; Julius, D. Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nat. Neurosci. 2008, 11, 772–779. [Google Scholar] [CrossRef]
  88. Tsunozaki, M.; Lennertz, R.C.; Vilceanu, D.; Katta, S.; Stucky, C.L.; Bautista, D.M. A ‘toothache tree’ alkylamide inhibits Aδ mechanonociceptors to alleviate mechanical pain. J. Physiol. 2013, 591, 3325–3340. [Google Scholar] [CrossRef]
  89. Tan, F.; Xu, L.; Liu, Y.; Li, H.; Zhang, D.; Qin, C.; Han, Y.; Han, J. Design of hydroxy-α-sanshool loaded nanostructured lipid carriers as a potential local anesthetic. Drug Deliv. 2022, 29, 743–753. [Google Scholar] [CrossRef]
  90. Ley, J.P.; Hilmer, J.M.; Weber, B.; Krammer, G.; Gatfield, I.L.; Bertram, H.J. Stereoselective enzymatic synthesis of cis-pellitorine, a taste active alkamide naturally occurring in Tarragon. Eur. J. Org. Chem. 2004, 2004, 5135–5140. [Google Scholar] [CrossRef]
  91. Oh, U.; Hwang, S.W.; Kim, D. Capsaicin activates a nonselective cation channel in cultured neonatal rat dorsal root ganglion neurons. J. Neurosci. 1996, 16, 1659–1667. [Google Scholar] [CrossRef] [PubMed]
  92. Li, Y.F.; Zhang, Y.G.; Bian, T.T.; Niu, J.; Si, X.; Cao, R.; Zhang, S.J.; Yan, X.K. Study on conduction anesthesia of water extract from different processed products of Zanthoxylum bungeanum. Chin. J. Clin. Pharmacol. 2021, 744, 727–729. [Google Scholar]
  93. Galopin, C.C.; Furrer, S.M.; Goeke, A. Pungent and tingling compounds in Asian cuisine. ACS Symp. Ser 2003, 867, 139–152. [Google Scholar]
  94. Menozzi-Smarrito, C.; Riera, C.E.; Munari, C.; Le Coutre, J.; Robert, F. Synthesis and evaluation of new alkylamides derived from alpha-hydroxysanshool, the pungent molecule in szechuan pepper. J. Agric. Food Chem. 2009, 57, 1982–1989. [Google Scholar] [CrossRef] [PubMed]
  95. Munekage, M.; Kitagawa, H.; Ichikawa, K.; Watanabe, J.; Aoki, K.; Kono, T.; Hanazaki, K. Pharmacokinetics of daikenchuto, a traditional Japanese medicine (kampo) after single oral administration to healthy Japanese volunteers. Drug Metab. Dispos. 2011, 39, 1784–1788. [Google Scholar] [CrossRef]
  96. Rong, R.; Cui, M.Y.; Zhang, Q.L.; Zhang, M.Y.; Yu, Y.M.; Zhou, X.Y.; Yu, Z.G.; Zhao, Y.L. Anesthetic constituents of Zanthoxylum bungeanum Maxim.: A pharmacokinetic study. J. Sep. Sci. 2016, 39, 2728–2735. [Google Scholar] [CrossRef]
  97. Tang, M.; Wang, Z.; Zhou, Y.; Xu, W.; Li, S.; Wang, L.; Wei, D.; Qiao, Z. A novel drug candidate for Alzheimer’s disease treatment: Gx-50 derived from Zanthoxylum bungeanum. J. Alzheimer’s Dis. 2013, 34, 203–213. [Google Scholar] [CrossRef]
  98. Meng, J.; Qian, D.; Li, R.L.; Peng, W.; Ai, L. In vitro metabolism and in vivo pharmacokinetics profiles of hydroxy-α-sanshool. Toxics 2024, 12, 100. [Google Scholar] [CrossRef]
  99. Matthias, A.; Gillam, E.M.; Penman, K.G.; Matovic, N.J.; Bone, K.M.; De Voss, J.J.; Lehmann, R.P. Cytochrome P450 enzyme-mediated degradation of Echinacea alkylamides in human liver microsomes. Chem. Biol. Interact. 2005, 155, 62–70. [Google Scholar] [CrossRef]
  100. Toselli, F.; Matthias, A.; Bone, K.M.; Gillam, E.M.; Lehmann, R.P. Metabolism of the major Echinacea alkylamide N-isobutyldodeca-2E,4E,8Z,10Z-tetraenamide by human recombinant cytochrome P450 enzymes and human liver microsomes. Phytother. Res. 2010, 24, 1195–1201. [Google Scholar] [CrossRef]
  101. Dubuisson, D.; Dennis, S.G. The formalin test: A quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 1977, 4, 161–174. [Google Scholar] [CrossRef]
  102. Shields, S.D.; Cavanaugh, D.J.; Lee, H.; Anderson, D.J.; Basbaum, A.I. Pain behavior in the formalin test persists after ablation of the great majority of C-fiber nociceptors. Pain 2010, 151, 422–429. [Google Scholar] [CrossRef]
Ijms 25 12228 g001
Figure 1. Chemical structures of alkamides in Z. piperitum.
Figure 1. Chemical structures of alkamides in Z. piperitum.
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Ijms 25 12228 g002
Figure 2. Chemical structures of alkamides in Z. bungeanum.
Figure 2. Chemical structures of alkamides in Z. bungeanum.
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Figure 3. Chemical structures of alkamides 38 and 39 in Z. lemairie, 40–42 in Z. Integrifoliolum, 43–45 in Z. ailanthoides and 46–49 in Z. armatum.
Figure 3. Chemical structures of alkamides 38 and 39 in Z. lemairie, 40–42 in Z. Integrifoliolum, 43–45 in Z. ailanthoides and 46–49 in Z. armatum.
Ijms 25 12228 g003
Ijms 25 12228 g004aIjms 25 12228 g004b
Figure 4. Chemical structures of alkamides 50–61 in Z. nitidum (Roxb.) DC., 62–66 in Z. nitidum var. tomentosum, 67 and 68 in Z. heitzii, 69 and 70 in Z. zanthoxyloides and 71 in Z. chalybeum.
Figure 4. Chemical structures of alkamides 50–61 in Z. nitidum (Roxb.) DC., 62–66 in Z. nitidum var. tomentosum, 67 and 68 in Z. heitzii, 69 and 70 in Z. zanthoxyloides and 71 in Z. chalybeum.
Ijms 25 12228 g004aIjms 25 12228 g004b
Ijms 25 12228 g005
Figure 5. Structural characteristics of alkamides that influence sensory properties of modulation, analgesic effect and local anesthetic effect.
Figure 5. Structural characteristics of alkamides that influence sensory properties of modulation, analgesic effect and local anesthetic effect.
Ijms 25 12228 g005
Table 1. Alkamides from Zanthoxylum species with dysfunctional sensory properties, analgesic or local anesthetic effect.
Table 1. Alkamides from Zanthoxylum species with dysfunctional sensory properties, analgesic or local anesthetic effect.
AlkamidesSensory Properties, Analgesic and Local Anesthetic EffectReferences
α-sanshool (1)
Ijms 25 12228 i001		The pungent qualities: burning, tingling and numbing.
Burning and tingling were predominantly perceived and lasting longer than numbness.		[84]
Hydroxy-α-sanshool (HAS) (2)
Ijms 25 12228 i002		Numbness: during treatment of toothache.
Inducing: insensitive to innocuous thermal or tactile stimuli; insensitive to touch or cooling.		[85]
Analgesia: during treatment of toothache.
Tingling and numbing.		[84]
Promoting Ca2+ influx in cells transfected with TRPV1 and evoked robust inward currents in cells transfected with TRPV1 in dorsal root ganglia neurons and trigeminal ganglion neurons.[86]
Exciting sensory neurons by inhibiting two-pore-domain K+ channels (KCNK3, KCNK9 and KCNK18).[87]
Inhibiting the activity of multiple voltage-gated sodium channel subtypes, among which Nav1.7 is the most strongly affected.
Inhibiting Aδ mechanonociceptors that mediate both sharp acute and inflammatory pain.		[88]
HAS + nanostructured lipid carriers had excellent anesthetic effect at low dose in formalin test compared with free HAS only and lidocaine: worked rapidly and sustained longer effect time.[89]
β-sanshool (3)
Ijms 25 12228 i003		The pungent qualities: numbing and bitter.[84]
Hydroxy-β-sanshool (13)
Ijms 25 12228 i004		The pungent qualities: numbing, astringent and bitter.
Mediating numbing and anesthetic effect.		[61]
γ-sanshool (43)
Ijms 25 12228 i005		The pungent qualities: burning, numbing, fresh, bitter.[84]
Burning and fresh.
Potent agonist of TRPV1 activity that explains its pungent and tingling sensation and its use as a natural anesthetic for toothache.		[84]
Hydroxy-γ-isosanshool (14)
Ijms 25 12228 i006		Inducing numbing and anesthetic effect.[61]
Hydroxy-ε-sanshool (5)
Ijms 25 12228 i007		Tingling sensations when applied to the human tongue.[85]
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Lu, I.-C.; Hu, P.-Y.; Lin, C.-H.; Chang, L.-L.; Wang, H.-C.; Cheng, K.-I.; Gau, T.-P.; Lin, K.-W. Alkamides in Zanthoxylum Species: Phytochemical Profiles and Local Anesthetic Activities. Int. J. Mol. Sci. 2024, 25, 12228. https://doi.org/10.3390/ijms252212228

AMA Style

Lu I-C, Hu P-Y, Lin C-H, Chang L-L, Wang H-C, Cheng K-I, Gau T-P, Lin K-W. Alkamides in Zanthoxylum Species: Phytochemical Profiles and Local Anesthetic Activities. International Journal of Molecular Sciences. 2024; 25(22):12228. https://doi.org/10.3390/ijms252212228

Chicago/Turabian Style

Lu, I-Cheng, Pin-Yang Hu, Chia-Heng Lin, Lin-Li Chang, Hung-Chen Wang, Kuang-I Cheng, Tz-Ping Gau, and Kai-Wei Lin. 2024. "Alkamides in Zanthoxylum Species: Phytochemical Profiles and Local Anesthetic Activities" International Journal of Molecular Sciences 25, no. 22: 12228. https://doi.org/10.3390/ijms252212228

APA Style

Lu, I. -C., Hu, P. -Y., Lin, C. -H., Chang, L. -L., Wang, H. -C., Cheng, K. -I., Gau, T. -P., & Lin, K. -W. (2024). Alkamides in Zanthoxylum Species: Phytochemical Profiles and Local Anesthetic Activities. International Journal of Molecular Sciences, 25(22), 12228. https://doi.org/10.3390/ijms252212228

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