Echinacea purpurea against neuropathic pain: Alkamides versus polyphenols efficacy.

Chemotherapy-induced neuropathy represents the main dose-limiting toxicity of several anticancer drugs, such as oxaliplatin, leading to chronic pain and an impairment of the quality of life. Echinacea purpurea n-hexane extract (EP4 -RE ; rich in alkamides) and butanolic extract (EP4 -RBU ; rich in polyphenols) have been characterized and tested in an in vivo model of oxaliplatin-induced neuropathic pain, addressing the endocannabinoid system with alkamides and counteracting the redox imbalance with polyphenols. Thermal hypersensitivity was evaluated by the Cold Plate test. EP4 -RE showed a dose-dependent anti-hyperalgesic profile. The extract was more effective than its main constituent, dodeca-2 E,4 E,8Z,10 E/Z-tetraenoic acid isobutylamide (18 mg kg-1 , twofold to equimolar EP4 -RE 30 mg kg-1 ), suggesting a synergy with other extract constituents. Administration of cannabinoid type 2 (CB2) receptor-selective antagonist completely blocked the anti-allodynic effect of EP4 -RE , differently from the antagonism of CB1 receptors. EP4 -RBU (30 mg kg-1 ) exhibited anti-neuropathic properties too. The effect was mainly exerted by chicoric acid, which administered alone (123 µg kg-1 , equimolar to EP4 -RBU 30 mg kg-1 ) completely reverted oxaliplatin-induced allodynia. A synergy between different polyphenols in the extract had not been highlighted. Echinacea extracts have therapeutic potential in the treatment of neuropathic pain, through both alkamides CB2-selective activity and polyphenols protective properties.

Neuroprotective Alkamides from the Aerial Parts of Achillea alpina L.

Three new alkamides, achilleamide B-D (1-3) along with five known alkamides (4-8) were isolated from the aerial parts of Achillea alpina L. Structures were elucidated by spectroscopic analysis. Modified Mosher's method and electronic circular dichroism (ECD) calculations were introduced for the absolute configuration of 3. The neuroprotective effects of all the compounds were evaluated by 6-hydroxydopamine (6-OHDA)-induced cell death in human neuroblastoma SH-SY5Y cells, with concentration for 50 % of maximal effect (EC50 ) values of 3.16-24.75 µM, and the structure-activity relationship was conducted.

Affinin and hexahydroaffinin: Chemistry and toxicological profile.

The present work aimed to determine the safety parameters of two new alkamides, affinin and hexahydroaffinin, with antinociceptive activity. To predict the preliminary acute toxicity, we used the acute and subchronic toxicity (50 mg/kg, orally [po]) in Swiss Webster mice. Genotoxicity assayed via analysis of cell micronuclei of the femoral bone marrow in mice; at the same time, metabolic parameters determined from peripheral blood samples. Furthermore, to discard the neuropharmacological effects, we assessed the ambulatory activity in mice to determine the possible effects in the central nervous system. Finally, we used capsaicin as a positive control of alkamides. According to our results, hexahydroaffinin (LD50 ≥ 5,000 mg/kg, po) is significantly less noxious than affinin (LD50 = 1,442.2 mg/kg, po) or capsaicin (LD50 = 489.9 mg/kg, po). In subchronic administration, we did not observe any changes in hematological or biochemical parameters in any compound analyzed from peripheral blood samples. Finally, the data from the genotoxicity assay showed micronuclei formation in 28%, 5%, and 3% of mice in the capsaicin, affinin, and hexahydroaffinin groups, respectively. With the results obtained in the present investigation, we suggest that affinin and hexahydroaffinin are not only useful candidates for possible new drugs but also safe compounds.

Antifungal and anti-aflatoxigenic activity of Heliopsis longipes roots and affinin/spilanthol against Aspergillus parasiticus by downregulating the expression of alfD and aflR genes of the aflatoxins biosynthetic pathway.

In the present study, ethanolic extract from Heliopsis longipes roots and affinin/spilanthol against Aspergillus parasiticus growth and aflatoxins production were studied in relation to the expression of aflD and aflR, two key genes of aflatoxins biosynthetic pathway. Phytochemical analysis of the ethanolic extract by GC-EIMS identified affinin/spilanthol (7.84 ± 0.27 mg g-1) as the most abundant compounds in H. longipes roots. The antifungal and anti-aflatoxigenic assays showed that affinin/spilanthol at 300 µg mL-1 produced the higher inhibition of radial growth (95%), as well as, the higher aflatoxins production inhibition (61%) in comparison to H. longipes roots (87% and 48%, respectively). qRT-PCR revealed that the expression of aflD and aflR genes showed a higher downregulation in affinin/spilanthol at 300 µg mL-1. The expression ratio of alfD was suppressed by affinin/spilanthol in 79% and aflR in 84%, while, a lower expression ratio suppressed by H. longipes was obtained, alfD (55%) and aflR (59%). Affinin/spilanthol possesses higher antifungal and anti-aflatoxigenic activity against A. parasiticus rather than H. longipes roots, and this anti-aflaxotigenic activity occurring via downregulation of the aflD and aflR genes. Thus, H. longipes roots and affinin/spilanthol can be considered potent antifungal agents against aflatoxigenic fungus, especially, affinin/spilanthol.

1 H and 13 C NMR data, occurrence, biosynthesis, and biological activity of Piper amides.

Alkamides are the major and characteristic chemical compounds of the plants belonging to the Piper genus. These compounds are responsible for the flavor of pepper spices and for its broad use in cuisine across many regions of the world. Humans are in contact every day with these substances, which additionally show a broad variety of pharmacological activities, making them an important research target. A large amount of NMR data for these natural products is dispersed throughout literature. Its organization will help those research groups interested in their identification and structural elucidation. This review summarizes the 1 H and 13 C NMR data of 268 Piper amides in a systematic and orderly way, with a discussion on their biological activities, biosynthetic aspects, and NMR analysis of typical and relevant aspects of this information.

Integrating metabolomics and transcriptomics data to discover a biocatalyst that can generate the amine precursors for alkamide biosynthesis.

The Echinacea genus is exemplary of over 30 plant families that produce a set of bioactive amides, called alkamides. The Echinacea alkamides may be assembled from two distinct moieties, a branched-chain amine that is acylated with a novel polyunsaturated fatty acid. In this study we identified the potential enzymological source of the amine moiety as a pyridoxal phosphate-dependent decarboxylating enzyme that uses branched-chain amino acids as substrate. This identification was based on a correlative analysis of the transcriptomes and metabolomes of 36 different E. purpurea tissues and organs, which expressed distinct alkamide profiles. Although no correlation was found between the accumulation patterns of the alkamides and their putative metabolic precursors (i.e., fatty acids and branched-chain amino acids), isotope labeling analyses supported the transformation of valine and isoleucine to isobutylamine and 2-methylbutylamine as reactions of alkamide biosynthesis. Sequence homology identified the pyridoxal phosphate-dependent decarboxylase-like proteins in the translated proteome of E. purpurea. These sequences were prioritized for direct characterization by correlating their transcript levels with alkamide accumulation patterns in different organs and tissues, and this multi-pronged approach led to the identification and characterization of a branched-chain amino acid decarboxylase, which would appear to be responsible for generating the amine moieties of naturally occurring alkamides.

Secondary Metabolic Profiles of Two Cultivars of Piper nigrum (Black Pepper) Resulting from Infection by Fusarium solani f. sp. piperis.

Bragantina and Cingapura are the main black pepper (Piper nigrum L.) cultivars and the Pará state is the largest producer in Brazil with about 90% of national production, representing the third largest production in the world. The infection of Fusarium solani f. sp. piperis, the causal agent of Fusarium disease in black pepper, was monitored on the cultivars Bragantina (susceptible) and Cingapura (tolerant), during 45 days' post infection (dpi). Gas Chromatography-Mass spectrometry (GC-MS) analysis of the volatile concentrates of both cultivars showed that the Bragantina responded with the production of higher contents of α-bisabolol at 21 dpi and a decrease of elemol, mostly at 30 dpi; while Cingapura displayed an decrease of δ-elemene production, except at 15 dpi. The phenolic content determined by the Folin Ciocalteu method showed an increase in the leaves of plants inoculated at 7 dpi (Bragantina) and 7-15 dpi (Cingapura); in the roots, the infection caused a phenolic content decrease in Bragantina cultivar at 45 dpi and an increase in the Cingapura cultivar at 15, 30 and 45 dpi. High Performance Liquid Chromatography-Mass spectrometry (HPLC-MS) analysis of the root extracts showed a qualitative variation of alkamides during infection. The results indicated that there is a possible relationship between secondary metabolites and tolerance against phytopathogens.

Comprehensive review of the phytochemistry, pharmacology, pharmacokinetics, and toxicology of alkamides (2016-2022).

Alkamides refer to a class of natural active small-molecule products composed of fatty acids and amine groups. These compounds are widely distributed in plants, and their unique structures and various pharmacological activities have caught the attention of scholars. This review provides a collection of literatures related to the phytochemistry, pharmacological effects, pharmacokinetics, and toxicity of alkamides published in 2016-2022 and their summary to provide references for further development of this class of ingredients. A total of 234 components (including chiral isomers) were summarized, pharmacological activities, such as anti-inflammatory, antitumor, antidiabetic, analgesic, neuroprotective, insecticidal, antioxidant, and antibacterial, and miscellaneous properties of alkamides were discussed. In addition, the pharmacokinetic characteristics and toxicity of alkamides were reviewed. However, information on the pharmacological mechanisms of the action, drug safety, and pharmacokinetics of alkamides is limited and thus requires further investigation and evaluation.

Alkylamides from Acmella oleracea: antinociceptive effect and molecular docking with cannabinoid and TRPV1 receptors.

Alkylamides are secondary metabolites in Acmella oleracea and display wide applications in treating several diseases. Since alkylamides can inhibit pain, this work aims to evaluate the antinociceptive profile of A. Oleracea methanolic extracts used in vivo and in silico assays. The extracts inhibited the neurogenic and inflammatory phases of the formalin test, ratifying the antinociceptive effect of alkylamides. Furthermore, the results from molecular docking demonstrated the interaction of A. oleracea alkylamides with the CB1/CB2 and TRPV1 receptors. Additionally, the crude methanolic extract of flowers did not induce potential side effects related to the classical cannabinoid tetrad: hypolocomotion and catalepsy. In conclusion, this work confirms the potential of the alkylamides of A. Oleracea as antinociceptive agents and, for the first time, correlates its effects with the endocannabinoid and vanilloid systems through in silico assays.

New ent-kaurene-type nor-diterpene and other compounds isolated from Annona vepretorum Mart. (Annonaceae).

A new nor-ent-kaurene diterpene and ten other compounds were isolated from Annona vepretorum stems, including four kaurene diterpenes, three alkamides, one sesquiterpene and two steroids. Their chemical structures were elucidated using spectroscopic methods, including 1D-, 2D-NMR, and HRESIMS. The absolute configuration of compounds 1, 5, 8, 9 and 10 was confirmed by CD experiments. Compounds 1-5 and 8-10 were evaluated for cytotoxic activity using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT method, against three human carcinoma cell lines: human colon (HCT-116), glioblastoma (SF295) and prostate (PC3). However, all isolated compounds exhibited low cytotoxic activity.

Antifungal and Antibiofilm Activity of Riparin III against Dermatophytes.

The ability of dermatophytes to develop biofilms is possibly involved in therapeutic failure because biofilms impair drug effectiveness in the infected tissues. Research to find new drugs with antibiofilm activity against dermatophytes is crucial. In this way, riparins, a class of alkaloids that contain an amide group, are promising antifungal compounds. In this study, we evaluated the antifungal and antibiofilm activity of riparin III (RIP3) against Trichophyton rubrum, Microsporum canis, and Nannizzia gypsea strains. We used ciclopirox (CPX) as a positive control. The effects of RIP3 on fungal growth were evaluated by the microdilution technique. The quantification of the biofilm biomass in vitro was assessed by crystal violet, and the biofilm viability was assessed by quantifying the CFU number. The ex vivo model was performed on human nail fragments, which were evaluated by visualization under light microscopy and by quantifying the CFU number (viability). Finally, we evaluated whether RIP3 inhibits sulfite production in T. rubrum. RIP3 inhibited the growth of T. rubrum and M. canis from 128 mg/L and N. gypsea from 256 mg/L. The results showed that RIP3 is a fungicide. Regarding antibiofilm activity, RIP3 inhibited biofilm formation and viability in vitro and ex vivo. Moreover, RIP3 inhibited the secretion of sulfite significantly and was more potent than CPX. In conclusion, the results indicate that RIP3 is a promising antifungal agent against biofilms of dermatophytes and might inhibit sulfite secretion, one relevant virulence factor.

Green synthesis of Piper nigrum copper-based nanoparticles: in silico study and ADMET analysis to assess their antioxidant, antibacterial, and cytotoxic effects.

Nanobiotechnology is a popular branch of science that is gaining interest among scientists and researchers as it allows for the green manufacturing of nanoparticles by employing plants as reducing agents. This method is safe, cheap, reproducible, and eco-friendly. In this study, the therapeutic property of Piper nigrum fruit was mixed with the antibacterial activity of metallic copper to produce copper nanoparticles. The synthesis of copper nanoparticles was indicated by a color change from brown to blue. Physical characterization of Piper nigrum copper nanoparticles (PN-CuNPs) was performed using UV-vis spectroscopy, FT-IR, SEM, EDX, XRD, and Zeta analyzer. PN-CuNPs exhibited potential antioxidant, antibacterial, and cytotoxic activities. PN-CuNPs have shown concentration-dependent, enhanced free radical scavenging activity, reaching maximum values of 92%, 90%, and 86% with DPPH, H2O2, and PMA tests, respectively. The antibacterial zone of inhibition of PN-CuNPs was the highest against Staphylococcus aureus (23 mm) and the lowest against Escherichia coli (10 mm). PN-CuNPs showed 80% in vitro cytotoxicity against MCF-7 breast cancer cell lines. Furthermore, more than 50 components of Piper nigrum extract were selected and subjected to in silico molecular docking using the C-Docker protocol in the binding pockets of glutathione reductase, E. coli DNA gyrase topoisomerase II, and epidermal growth factor receptor (EGFR) tyrosine to discover their druggability. Pipercyclobutanamide A (26), pipernigramide F (32), and pipernigramide G (33) scored the highest Gibbs free energy at 50.489, 51.9306, and 58.615 kcal/mol, respectively. The ADMET/TOPKAT analysis confirmed the favorable pharmacokinetics, pharmacodynamics, and toxicity profiles of the three promising compounds. The present in silico analysis helps us to understand the possible mechanisms behind the antioxidant, antibacterial, and cytotoxic activities of CuNPs and recommends them as implicit inhibitors of selected proteins.

Solanum lycopersicum Seedlings. Metabolic Responses Induced by the Alkamide Affinin.

Alkamides have been observed to interact in different ways in several superior organisms and have been used in traditional medicine in many countries e.g., to relieve pain. Previous studies showed that affinin when applied to other plant species induces prominent changes in the root architecture and induces transcriptional adjustments; however, little is known about the metabolic pathways recruited by plants in response to alkamides. Previous published work with Arabidopsis seedlings treated in vitro with affinin at 50 µM significantly reduced primary root length. In tomato seedlings, that concentration did not reduce root growth but increase the number and length of lateral roots. Non-targeted metabolomic analysis by Gas Chromatography couplet to Mass Spectrometry (GC/EIMS) showed that, in tomato seedlings, affinin increased the accumulation of several metabolites leading to an enrichment of several metabolic pathways. Affinin at 100 µM alters the accumulation of metabolites such as organic acids, amino acids, sugars, and fatty acids. Finally, our results showed a response possibly associated with nitrogen, GABA shunt and serine pathways, in addition to a possible alteration in the mitochondrial electron transport chain (ETC), interesting topics to understand the molecular and metabolic mechanisms in response to alkamide in plants.

(E)-Piplartine Isolated from Piper pseudoarboreum, a Lead Compound against Leishmaniasis.

The current therapies of leishmaniasis, the second most widespread neglected tropical disease, have limited effectiveness and toxic side effects. In this regard, natural products play an important role in overcoming the current need for new leishmanicidal agents. The present study reports a bioassay-guided fractionation of the ethanolic extract of leaves of Piper pseudoarboreum against four species of Leishmania spp. promastigote forms, which afforded six known alkamides (1-6). Their structures were established on the basis of spectroscopic and spectrometric analysis. Compounds 2 and 3 were identified as the most promising ones, displaying higher potency against Leishmania spp. promastigotes (IC50 values ranging from 1.6 to 3.8 µM) and amastigotes of L. amazonensis (IC50 values ranging from 8.2 to 9.1 µM) than the reference drug, miltefosine. The efficacy of (E)-piplartine (3) against L. amazonensis infection in an in vivo model for cutaneous leishmaniasis was evidenced by a significant reduction of the lesion size footpad and spleen parasite burden, similar to those of glucantime used as the reference drug. This study reinforces the therapeutic potential of (E)-piplartine as a promising lead compound against neglected infectious diseases caused by Leishmania parasites.

Macamides: A review of structures, isolation, therapeutics and prospects.

Macamides, the major bioactive compounds of Lepidium meyenii (Walp.) or Maca, are a unique class of non-polar, long chain fatty acid N-benzylamides with fertility-enhancing, neuroprotective, neuro-modulatory, anti-fatigue and anti-osteoporosis effects. However, the relationship between the structures and pharmacological effects of macamides have not been established so far. In addition, little is known regarding their biosynthetic pathways and the mechanisms underlying the biological activities. In this review, we have summarized the methods currently used for the extraction, purification and synthesis of macamides. Their pharmacological effects, clinical prospects and biomedical applications have also been discussed. Current data strongly suggest that macamides are a promising bio-active agent, and further studies are warranted to elucidate their mechanisms of action.

Global gene expression analyses of the alkamide-producing plant Heliopsis longipes supports a polyketide synthase-mediated biosynthesis pathway.

BACKGROUND: Alkamides are plant-specific bioactive molecules. They are low molecular weight N-substituted α-unsaturated acyl amides that display biological explicit activities in different organisms from bacteria, fungi, insects to mammals and plants. The acyl chain has been proposed to be biosynthesized from a fatty acid; however, this has not been demonstrated yet. Heliopsis longipes (Asteraceae) accumulates in root a C10 alkamide called affinin in its roots, but not in leaves. The closely related species Heliopsis annua does not produce alkamides. To elucidate the biosynthetic pathway of the alkamides acyl chain, a comparative global gene expression analysis contrasting roots and leaves of both species was performed. METHODS: Transcriptomics analysis allowed to identify genes highly expressed in H. longipes roots, but not in tissues and species that do not accumulate alkamides. The first domain searched was the Ketosynthase (KS) domain. The phylogenetic analysis using sequences of the KS domain of FAS and PKS from different organisms, revealed that KS domains of the differentially expressed transcripts in H. longipes roots and the KS domain found in transcripts of Echinacea purpurea, another alkamides producer species, were grouped together with a high bootstrap value of 100%, sharing great similarity. Among the annotated transcripts, we found some coding for the enzymatic domains KS, AT, ACP, DH, OR and TE, which presented higher expression in H. longipes roots than in leaves. The expression level of these genes was further evaluated by qRT-PCR. All unigenes tested showed higher expression in H. longipes roots than in any the other samples. Based on this and considering that the acyl chain of affinin presents unsaturated bonds at even C numbers, we propose a new putative biosynthesis pathway mediated by a four modules polyketide synthase (PKS). RESULTS: The global gene expression analysis led to the selection of a set of candidate genes involved in the biosynthesis of the acyl chain of affinin, suggesting that it may be performed by a non-iterative, partially reductive, four module type I PKS complex (PKS alk) previously thought to be absent from the plant kingdom.

Fatty Acid Amide Hydrolases: An Expanded Capacity for Chemical Communication?

Fatty acid amide hydrolase (FAAH) is an enzyme that belongs to the amidase signature (AS) superfamily and is widely distributed in multicellular eukaryotes. FAAH hydrolyzes lipid signaling molecules - namely, N-acylethanolamines (NAEs) - which terminates their actions. Recently, the crystal structure of Arabidopsis thaliana FAAH was solved and key residues were identified for substrate-specific interactions. Here, focusing on residues surrounding the substrate-binding pocket, a comprehensive analysis of FAAH sequences from angiosperms reveals a distinctly different family of FAAH-like enzymes. We hypothesize that FAAH, in addition to its role in seedling development, also acts in an N-acyl amide communication axis to facilitate plant-microbe interactions and that structural diversity provides for the flexible use of a wide range of small lipophilic signaling molecules.

Glucosinolate catabolism during postharvest drying determines the ratio of bioactive macamides to deaminated benzenoids in Lepidium meyenii (maca) root flour.

Postharvest processing of maca (Lepidium meyenii Walp., Brassicaceae), a traditional high-altitude Andean root crop, involves slow field drying prior to milling into flour. The progressive tissue dehydration and release of hydrolytic enzymes and substrates from cellular compartments results in the slow accumulation of free monosaccharides, fatty acids and amino acids. A more complex, and faster, kinetic profile is that of glucosinolate breakdown. A number of reactive transient and stable accumulation products are generated during drying, some of which have noteworthy bioactive properties. Among these are macamides, inhibitors of endocannabinoid neurotransmitter degradation in mammalian nervous systems. They result from the condensation of benzyl amine, a glucosinolate hydrolysis product, with free fatty acids released from lipid hydrolysis. Recent research has focused on developing drying processes under controlled conditions that can modulate the biochemistry of glucosinolate hydrolysis to optimize the content of bioactive compounds in the root flour. Low temperature (35 °C) oven-drying of shredded maca roots under controlled air flow generates benzyl amine as primary accumulation product, accounting for up to 94% of hydrolyzed glucosinolate in the flour. Kinetic evidence suggests that both deaminated benzenoids and macamides are allocated from the benzylamine pool through amine oxidase activity or condensation with free fatty acids, accounting for the remaining hydrolyzed glucosinolate (<5%). These activities determine the allocation to either one of these pathways. Later stages of dehydration result in shifts in the molar ratios of deaminated benzenoids, the accumulation of benzoic acid esters and benzyl alcohol. We propose that these are the result of changes in the rates of the reductive and oxidative half-reactions of endogenous aldehyde dehydrogenases. It is the ratio of benzylamine deamination to amide formation that determines the eventual yields of macamides in relation to benzenoids and their esters in maca flour.

Alkamides from Tropaeolum tuberosum inhibit inflammatory response induced by TNF-α and NF-κB.

ETHNO-PHARMACOLOGICAL RELEVANCE: Tropaeolum tuberosum, commonly known as "Mashua", is one of the plants most frequently used by Andean (Peruvian-Bolivian) people as food and medicine. It is used as a remedy against a wide range of diseases, especially those related with inflammation. OBJECTIVES: This study aims to identify compounds active against inflammatory related conditions. MATERIALS AND METHODS: A bioassay-guided isolation of anti-inflammatory compounds from black and purple tubers of T. tuberosum was performed measuring TNF-α and NF-κB production in THP-1 monocytic cells. RESULTS: The bioassay-guided isolation led to one active compound from purple T. tuberosum, N-oleoyldopamine (1), and another active compound from black T. tuberosum, N-(2-Hydroxyethyl)-7Z,10Z,13Z,16Z-docosatetraenamide (2). Both compounds displayed anti-TNF-α activity with IC50 values of 3.12 ±â€¯0.19 µM and 1.56 ±â€¯0.15 µM, respectively. Also, both compounds suppressed NF-κB with IC50 of 3.54 ±â€¯0.02 µM and 1.77 ±â€¯0.07 µM, respectively. CONCLUSIONS: We identified bioactive compounds from purple and black Tropaeolum tuberosum responsible for their anti-inflammatory activity: N-oleoyldopamine (1) and N-(2-Hydroxyethyl)-7Z,10Z,13Z,16Z-docosatetraenamide (2). This is the first report which isolates these compounds from T. tuberosum and describes their anti-inflammatory activities.

Piperine-like alkamides from Piper nigrum induce BDNF promoter and promote neurite outgrowth in Neuro-2a cells.

Black pepper (Piper nigrum) contains a variety of alkamides. Among them, piperine has been reported to have antidepressant-like effects in chronically stressed mice, but little is known about the biological activity of other alkamides. In this study, we investigated the effects of alkamides from white pepper (P. nigrum) on neuronal cells. Twelve alkamides were isolated from white pepper MeOH extracts, and their chemical structures were identified by NMR and MS analyses. The compounds were subjected to assays using the luciferase-reporter gene under the control of the BDNF promoter or cAMP response element in mouse neuroblastoma Neuro-2a cells. In both assays, marked reporter-inducing activity was observed for piperine (1), piperettine (2) and piperylin (7), all of which have in common an (E)-5-(buta-1,3-dien-1-yl)benzo[d] [1, 3] dioxole moiety. Piperettine (2) and piperylin (7) tended to increase endogenous BDNF protein levels. Furthermore, piperylin (7) promoted retinoic acid-induced neurite outgrowth. These results suggest that piperylin (7), or analogues thereof, may have a beneficial effect on disorders associated with dysregulation of BDNF expression, such as depression.