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The author discussed recently the possible molecular mechanisms that cause the COVID-19 disease symptoms. Here the analysis of the recent experimental data supports the hypothesis that production of the gut microbial tryptamine can be induced by the SARS-CoV-2 fecal viral activity due to the selective pressure or positive selection of tryptamine-producing microorganisms. In this report, the author suggests that the mechanism of microbial selection bases on the abilities of tryptamine to affect the viral nucleic acid. In other words, the gut microorganisms producing tryptamine are more resistant to SARS-CoV-2 fecal viral activity than microorganisms producing no tryptamine. Earlier we demonstrated the induction of neurodegeneration by tryptamine in human cells and mouse brain. Furthermore, we were able to uncover the human gut bacteria associated with Alzheimer’s disease (AD) using PCR testing of human fecal samples with the new-designed primers targeting the tryptophan-tryptamine pathway. Likely, SARS-CoV-2 is one of the selective pressure factors in the cascade accelerating the neurodegenerative process in AD. This suggestion is consistent with a higher proportion of AD patients among COVID-19 related victims. Gut microbial tryptamine increase due to the viral infection-induced dysbiosis can synergize and potentiate the tryptamine cytotoxicity, necrotizing ability and other properties as a virulence factor.

The interaction of selenium (Se) and melatonin in plants is unclear. The aim of this study was to investigate the effects of Se root application on melatonin synthesis in sweet cherry. Cultivar ‘Russia No.8’ was treated with Se6+ (sodium selenate) or Se2− (selenomethionine). Parameters of plant antioxidant levels, growth parameters, and the synthesis enzyme activities and precursor contents of melatonin were measured. Results showed that the plant benefited more from Se6+ than Se2− and were not exposed to Se stress by four low doses of Se6+ (0, 0.2, 0.4, and 0.6 mg kg−1) treatments for 40 days. The trends of tryptophan hydroxylase (TPH), tryptamine-5-hydroxylas, and arylalkylamine N-acetyltransferase activities were similar, while tryptophan decarboxylase (TDC), serotonin-N-acetyltransferase (SNAT), caffeic acid-O-methyltransferase, and N-acetyl-5-hydroxytryptamine-O-methyltransferase (ASMT) activities were different in leaves and roots following different Se6+ treatments. Tryptophan and 5-hydorxy tryptophan contents were not influenced by the Se6+ dose. Tryptamine was not detected in leaves or roots, but the serotonin content was increased by Se6+ treatment. The leaf content of N-acetyl-5-tryptophan was not influenced, but its synthesis was significantly induced in roots as the Se dose increased. Melatonin synthesis in leaves and roots was increased only following treatment with 96 mg Se6+. The leaf Se and melatonin content showed no significant linear relationship in the ‘Russia No.8’ cultivar. Treatment with Se2− increased the enzyme levels of TDC, TPH, SNAT, and ASMT more significantly than Se6+. Overall, lower doses of Se6+ did not significantly induce melatonin synthesis, but the relationship between melatonin and Se2− merits further attention.

Pantothenate synthetase from Escherichia coli (PSE. coli) catalyzes the ATP-dependent condensation of (R)-pantoic acid and β-alanine to yield (R)-pantothenic acid (vitamin B5), the biosynthetic precursor to coenzyme A. Herein we show that besides the natural amine substrate β-alanine, the enzyme accepts a wide range of structurally diverse amines including 3-amino-2-fluoropropionic acid, 4-amino-2-hydroxybutyric acid, 4-amino-3-hydroxybutyric acid, and tryptamine for coupling to the native carboxylic acid substrate (R)-pantoic acid to give amide products with up to >99% conversion. The broad amine scope of PSE. coli enabled the efficient synthesis of pharmaceutically-relevant vitamin B5 antimetabolites with excellent isolated yield (up to 89%). This biocatalytic amide synthesis strategy may prove to be useful in the quest for new antimicrobials that target coenzyme A biosynthesis and utilisation., Pantothenate synthetase from Escherichia coli (PSE. coli) has a broad substrate scope, accepting diverse amines in the amidation of (R)-pantoate, enabling the facile synthesis of pharmaceutically relevant vitamin B5 antimetabolites.

Background: COVID-19 can be related to any diseases caused by microbial infection(s) because 1) co-infection with COVID-19-related virus and other microorganism(s) and 2) because metabolites produced by microorganisms such as bacteria, fungi, and protozoan can be involved in necrotizing pneumonia and other necrotizing medical conditions observed in COVID-19. Objective: By way of illustration, the microbial metabolite of aromatic amino acid tryptophan, a biogenic amine tryptamine inducing neurodegeneration in cell and animal models, also induces necrosis. Methods: This report includes analysis of COVID-19 positivity by zip codes in Florida and relation of the positivity to population density, possible effect of ecological and social factors on spread of COVID-19, autopsy analysis of COVID-19 cases from around the world, serum metabolomics analysis, and evaluation of autoantigenome related to COVID-19. Results: In the present estimations, COVID-19 positivity percent per zip code population varied in Florida from 4.65% to 44.3% (February 2021 data). COVID-19 analysis is partially included in my book Microbial Metabolism and Disease (2021). The autoantigenome related to COVID-19 is characterized by alterations in protein biosynthesis proteins including aminoacyl-tRNA synthetases. Protein biosynthesis alteration is a feature of Alzheimer’s disease. Serum metabolomics of COVID-19 positive patients show alteration in shikimate pathway metabolism, which is associated with the presence of Alzheimer’s disease-associated human gut bacteria. Conclusion: Such alterations in microbial metabolism and protein biosynthesis can lead to toxicity and neurodegeneration as described earlier in my book Protein Biosynthesis Interference in Disease (2020).

By the reaction of thiophen-2-carbaldehyde with rhodanine derivatives, 5-thiophen-2-ylmethylene-2-thioxothiazolidin-4-ones have been synthesized. The resulting (4-oxo-5-thiophen-2-ylmethylen-2-thioxothiazolidin-3-yl)alkane carboxylic acids have been used to acylate the biogenic amine tryptamine and its derivatives. As a result, a number of novel N-[2-(5-[R-1H-indol-3-yl)-ethyl]-2-(4-oxo-5-thiophen-2-ylmethylen-2-thioxothiazolidin-3-yl)carbamides have been synthesized. The antimicrobial and antitumor properties of the resulting compounds have been tested. Compounds with a high antimicrobial activity against Staphylococcus aureus and Cryptococcus neoformans have been identified.

Rising numbers of psychoactive tryptamine derivatives have become available on the drug market over the last decade, making these naturally occurring or synthetically manufactured compounds highly relevant for forensic analyses. One of these compounds is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a constituent of the dried poison of Incilius alvarius (Colorado River toad), which has a history of ritual and/or recreational use. Still, comprehensive and validated qualitative as well as quantitative analytical data on the psychoactive components of this poison are scarce. In this study, samples of the poison of Incilius alvarius were collected from live toads in the Sonoran Desert, Arizona (USA), and analyzed with a set of complementary methods. Acetone/water (70/30, v/v) proved to be the solvent of choice for the extraction of tryptamine derivatives. Trace compounds were enriched, and overload with 5-MeO-DMT was prevented by chromatographic separation of 5-MeO-DMT prior to qualitative analyses. The method for quantification was validated. Attenuated total reflection–Fourier transform infrared spectroscopy was suitable to identify 5-MeO-DMT as the main tryptamine in samples of the poison. The combined evaluation of analytical data gained from gas chromatography–mass spectrometry (GC–MS), high-performance liquid chromatography–quadrupole time-of-flight high-resolution MS (HPLC–qToF-HRMS) and HPLC–MS-MS confirmed the presence of 5-MeO-DMT, 5-MeO-N-methyltryptamine, 5-MeO-tryptamine, 5-MeO-tryptophol, 2-(5-methoxy-1H-indol-3-yl)-acetic-acid (5-MIAA), 5-HO-N-methyltryptamine, bufotenin, DMT and tryptophan. For the first time, 5-MeO-tryptamine and two positional isomers of hydroxylated MeO-DMT were detected in the poison of Incilius alvarius. The tryptamine present in the highest concentrations was 5-MeO-DMT (mean ± SD: 410,000 ± 30,000 μg/g). Mean concentrations of 5-MeO-tryptamine (490 ± 260 μg/g), 5-HO-N-methyltryptamine (270 ± 120 μg/g), bufotenin (2,800 ± 1,900 μg/g) and DMT (250 ± 80 μg/g) showed a relatively high variability between individual samples. The comprehensive analytical reference data of Incilius alvarius poison presented here might prove useful for forensic chemists.

A novel analogue of psilocybin was produced by hybrid chemoenzymatic synthesis in sufficient quantity to enable bioassay. Utilizing purified 4-hydroxytryptamine kinase from Psilocybe cubensis, chemically synthesized 5-methylpsilocin (2) was enzymatically phosphorylated to provide 5-methylpsilocybin (1). The zwitterionic product was isolated from the enzymatic step with high purity utilizing a solvent–antisolvent precipitation approach. Subsequently, 1 was tested for psychedelic-like activity using the mouse head-twitch response assay, which indicated activity that was more potent than the psychedelic dimethyltryptamine, but less potent than that of psilocybin.

Indole-3-acetic acid (IAA) is a critical plant hormone that regulates cell division, development, and metabolism. IAA synthesis in plants and plant-associated microorganisms cannot fulfill the requirement for large-scale agricultural production. Here, two novel IAA biosynthesis pathways, tryptamine (TAM) and indole-3-acetamide (IAM), were developed for IAA production by whole-cell catalysis and de novo biosynthesis in an engineered Escherichia coli MG1655. When 10 g/L l-tryptophan was used as a substrate, an MIA-6 strain containing a heterologous IAM pathway had the highest IAA titer of 7.10 g/L (1.34 × 103 mg/g DCW), which was 98.4 times more than MTAI-5 containing the TAM pathway by whole-cell catalysis. De novo IAA biosynthesis was optimized by improving NAD(P)H availability, resulting in an increased IAA titer of 906 mg/L obtained by the MGΔadhE::icd strain, which is 29.7% higher than the control. These strategies exhibit the potential for IAA production in engineered E. coli and possible industrial applications.

Known classic psychedelic serotonin 2A receptor (5-HT(2A)R) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HT(2A)R can be elicited by drugs lacking these fundamental scaffolds. Such is the case of the N-substituted piperazine quipazine. Here, we show that quipazine bound to and activated 5-HT(2A)R as measured by [(3)H]ketanserin binding displacement, Ca(2+) mobilization, and accumulation of the canonical G(q/11) signaling pathway mediator inositol monophosphate (IP(1)) in vitro and in vivo. Additionally, quipazine induced via 5-HT(2A)R an expression pattern of immediate early genes (IEG) in the mouse somatosensory cortex consistent with that of classic psychedelics. In the mouse head-twitch response (HTR) model of psychedelic-like action, quipazine produced a lasting effect with high maximal responses during the peak effect that were successfully blocked by the 5-HT(2A)R antagonist M100907 and absent in 5-HT(2A)R knockout (KO) mice. The acute effect of quipazine on HTR appeared to be unaffected by serotonin depletion and was independent from 5-HT(3)R activation. Interestingly, some of these features were shared by its deaza bioisostere 2-NP, but not by other closely related piperazine congeners, suggesting that quipazine might represent a distinct cluster within the family of psychoactive piperazines. Together, our results add to the mounting evidence that quipazine’s profile matches that of classic psychedelic 5-HT(2A)R agonists at cellular signaling and behavioral pharmacology levels.

There is significant demand for the development of rapid, sensitive, and specific methods for detecting bacterial pathogens in order to identify the causes of food poisoning. Nucleic acid amplification tests (NAATs) allow for the culture-free detection of bacterial pathogens and are not as labor intensive and time consuming as culture-based detection methods. However, suitable sample preparation methods must be developed for the realization of simple, rapid, and sensitive NAATs. To resolve this problem, we developed a new sample preparation method that integrates bacterial pathogen enrichment and DNA extraction. We engineered magnetic nanoparticles (MNPs) with a physicochemical probe (tryptamine) for single-tube sample preparation with minimal sample loss. The tryptamine-functionalized MNPs (Indole@MNPs) showed inherent hydrophobicity owing to the indole side chain and a change in their zeta potential with a decrease in the pH. Because of their physicochemical characteristics, the Indole@MNPs could adsorb bacterial pathogens, thus allowing sample enrichment and DNA binding and release through weak electrostatic interactions via pH control. We successfully detected Salmonella enterica serovar Typhimurium, a common cause of bacterial food poisoning, at a concentration of 10 CFU/10 mL in milk samples using quantitative PCR. Thus, the proposed method allows for the simple and sensitive detection of Salmonella typhimurium and can be used for nontyphoidal salmonella detection to ensure food safety.

Curcumin (CUR) is used as a dietary and food supplement with medicinal properties. It has a wide range of therapeutic activities such as antioxidant, anti-inflammatory, anti-arthritis, anti-tumor, anti-hyperglycemic, anti-malarial, anti-bacterial, and antiviral properties. The low solubility of curcumin in aqueous medium (7.8 μg mL−1) and low bioavailability leads to its lack of use as an oral medicine. In this work, the use of basic amino acids and their biological derivatives to improve the physicochemical properties of curcumin is described. Binary adducts of CUR with tyramine, tryptamine, arginine, asparagine, glutamine, lysine, histidine, and citrulline were characterized by spectroscopic, thermal, X-ray and microscopic techniques. The solubility and dissolution of curcumin in 40% ethanol–water solution exhibited a considerable improvement for these binary products. The use of amino acids as additives to improve the solubility of CUR in medical supplements is described.

The azepinoindole framework present in natural alkaloids such as subincanadine F, ibogaine and catharanthine was formed in a novel acid-promoted cyclization-rearrangement of tryptamine-derived N-sulfonyl enamines. The latter were conveniently prepared via a cesium carbonate mediated formal vinylic substitution reaction of 2-bromoallyl sulfones (allenyl sulfone surrogate) and tryptamine sulfonamides. The azepinoindole forming cyclization-rearrangement involves the initial generation of a six-membered tetrahydro-β-carboline derivative. The steric bulk of the N-sulfonyl group on tryptamine plays an important role in deciding the reaction outcome.

The overuse of metallic oxide nanoparticles (NPs) has caused a burst of their enrichment in paddy fields. Several findings have reported that the NPs of ZnO and CuO have an adverse impact on plant growth, while the potential mechanism of rice response to the NPs of metallic oxides remains largely unknown. In our research, we found that pretreatment with different concentrations of ZnO and CuO NPs greatly increased the biosynthesis and accumulation of melatonin and its precursors (serotonin, tryptamine, and tryptophan), and induced the transcription of melatonin biosynthetic genes in rice seedlings. Foliage sprayed melatonin greatly enhanced the tolerance to metallic oxide NPs toxicity in rice plants as evidenced by reduced inhibition of plant growth and enhanced biosynthesis of tetrapyrrole in rice seedlings. Exogenous melatonin significantly alleviated metallic oxide NPs-induced oxidative stress with decreased reactive oxygen species (ROS), and increased the activity and gene expression of major antioxidant enzymes. Moreover, the melatonin supplement greatly increased the total amino acid content under metallic oxide NPs treatment in rice leaves. In summary, our findings reveal that melatonin is related to metallic oxide nanoparticle-participated molecular, biochemical, and physiological alterations by accelerating tetrapyrrole biosynthesis and amino acid metabolism in rice.

[Image: see text] The 5-HT(2A) receptor is thought to be the primary target for psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and other serotonergic hallucinogens (psychedelic drugs). Although a large amount of experimental work has been conducted to characterize the pharmacology of psilocybin and its dephosphorylated metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine), there has been little systematic investigation of the structure–activity relationships (SAR) of 4-substituted tryptamine derivatives. In addition, structural analogs of psilocybin containing a 4-acetoxy group, such as 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), have appeared as new designer drugs, but almost nothing is known about their pharmacological effects. To address the gap of information, studies were conducted with 17 tryptamines containing a variety of symmetrical and asymmetrical N,N-dialkyl substituents and either a 4-hydroxy or 4-acetoxy group. Calcium mobilization assays were conducted to assess functional activity at human and mouse 5-HT(2) subtypes. Head-twitch response (HTR) studies were conducted in C57BL/6J mice to assess 5-HT(2A) activation in vivo. All of the compounds acted as full or partial agonists at 5-HT(2) subtypes, displaying similar potencies at 5-HT(2A) and 5-HT(2B) receptors, but some tryptamines with bulkier N-alkyl groups had lower potency at 5-HT(2C) receptors and higher 5-HT(2B) receptor efficacy. In addition, O-acetylation reduced the in vitro 5-HT(2A) potency of 4-hydroxy-N,N-dialkyltryptamines by about 10- to 20-fold but did not alter agonist efficacy. All of the compounds induce head twitches in mice, consistent with an LSD-like behavioral profile. In contrast to the functional data, acetylation of the 4-hydroxy group had little effect on HTR potency, suggesting that O-acetylated tryptamines may be deacetylated in vivo, acting as prodrugs. In summary, the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.

To prevent the abuse of new designer drugs, Japan has declared 2385 substances and two plants as “Designated Substances” as of March 2020. Although the distribution of these substances has decreased over the past 5 years, newly detected designer drugs are still being found. We have detected six designer drugs in six powdery products between February of 2017 and April of 2019. The structures of the compounds were determined by gas chromatography mass spectrometry (GC–MS), liquid chromatography mass spectrometry (LC–MS), liquid chromatography with hybrid quadrupole time-of-flight mass spectrometry (LC-Q-TOF–MS) and nuclear magnetic resonance (NMR) spectroscopy. Six tryptamine derivatives (4-acetoxy-N,N-dipropyltryptamine, 4-hydroxy-N,N-dipropyltryptamine, 4-hydroxy-N-methyl-N-propyltryptamine, N-ethyl-N-propyltryptamine, 4-hydroxy-N-ethyl-N-propyltryptamine (4OH-EPT), and 4-hydroxy-N-methyl-N-cyclopropyltryptamine (4OH-McPT) were identified. Among these, 4OH-EPT and 4OH-McPT were identified as newly distributed designer drugs. The continuous provisional monitoring of newly detected compounds in illicit products will largely prevent the distribution of these products.

—Trace amines are similar in structure to catecholamines and serotonin of the central nervous system but are present at much lower concentrations. Trace amines such as tyramine, tryptamine, octopamine, and β-phenylethylamine, bind to highly specific receptors that have low affinity for catecholamines and serotonin. Several types of trace amine receptors have been identified. Trace amine-associated receptor 1 is localized in the prefrontal cortex and limbic structures. Localization of the other types of receptors is different. In particular, trace amine-associated receptor 5 is localized in the olfactory epithelium and structures of the olfactory brain. By interaction with dopaminergic and other neurotransmitter systems of the CNS, trace amines are involved in the regulation of many behavioral forms. In simplistic terms, we can talk about the functional antagonism of trace amines and the dopaminergic system. Trace amines are considered as promising antipsychotics, which is evidenced by the results of studies in animal models of schizophrenia.

New derivatives of chromeno[4,3-b]quinolin-6-one were synthesized using novel SO3H-tryptamine supported on Fe3O4@SiO2@CPS which could be recycled as an effective magnetic nanocatalyst. SEM, EDX, XRD, FT-IR, TGA, VSM and BET analyses were utilized to confirm the magnetic nanocatalyst structure. Evaluation of Antimicrobial (antibacterial and antifungal) function of magnetic nanocatalyst as well as derivatives undergone synthesis was carried out according to MIC, MBC and MFC values. Moreover, evaluation of the derivatives subject to synthesis was performed according to DPPH free radical besides the biological features, in order to obtain justifiable biological features.

Selenium (Se), an essential micronutrient for humans, is also a beneficial nutrient for growth and development of many plants. The aim of the present study was to determine whether low-dose Se application could increase plum growth and serotonin synthesis, as well as upregulate the glutathione redox cycle. Two-year-old plum trees were treated with Se6+ (Na2SeO4) and Se2− (SeMet). Growth parameters, levels of serotonin synthesis precursors, compounds and enzymes of the glutathione (GSH) redox cycle, and the antioxidant capacity were analyzed. Results showed that plant height and stem diameter were increased by Se treatment. The leaf Se content was significantly increased; tryptophan was not affected by Se treatment, while the 5-hydroxytryptophan content was significantly higher than control. Although serotonin levels were also increased, the effect was not significant, and no tryptamine was detected in our study. On the 30th day, the MDA content in Se2− was highest followed by the control and Se6+ treatment, and the activities of T-AOT and CAT were increased, while GST was reduced by Se treatment. The two forms of Se treatments increased the activity of GPX and GR, and the total content of GSH + glutathione disulfide (GSSG) at the end of treatment. Furthermore, the level of GSH and GSH/GSSG was instable changed. GSSG content was similar during the treatment time except on the 20 days. Conclusively, the pathway of plum serotonin was clear, both Se6+ and Se2− could influence the serotonin synthesis. Additionally, the GSH redox cycle was sensitive to the Se application. Moreover, Se6+ performed better than Se2− on leaf Se content, plant growth parameters, and antioxidant capacity.

A second-generation kilogram-scale synthesis of the psychedelic tryptamine psilocybin has been developed. The synthesis was designed to address several challenges first encountered with the scale-up of previously described literature procedures, which were not optimized for providing consistent yield and purity of products, atom economy, or being run in pilot plant-scale reactors. These challenges were addressed and circumvented with the design of the second-generation route, which featured an optimized cGMP large-scale Speeter-Anthony tryptamine synthesis to the intermediate psilocin with improved in-process control and impurity removal over the three steps. Psilocin was subsequently phosphorylated directly with phosphorous oxychloride for the first time, avoiding a tedious and poor atom economy benzyl-protecting group strategy common to all previously described methods for producing psilocybin. In this report, the challenges encountered in a 100 g scale first-generation literature-based synthesis are highlighted, followed by a detailed description of the newly developed second-generation synthesis to provide over one kilogram of high-purity psilocybin under cGMP.

Ultraviolet photodissociation (UVPD) experiments of protonated tryptamine ([Tryp+H]+) have been implemented by a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer combined with a ...

Psilocybin, the principal indole alkaloid of Psilocybe mushrooms, is currently undergoing clinical trials as a medication against treatment‐resistant depression and major depressive disorder. The psilocybin supply for pharmaceutical purposes is met by synthetic chemistry. We replaced the problematic phosphorylation step during synthesis with the mushroom kinase PsiK. This enzyme was biochemically characterized and used to produce one gram of psilocybin from psilocin within 20 minutes. We also describe a pilot‐scale protocol for recombinant PsiK that yielded 150 mg enzyme in active and soluble form. Our work consolidates the simplicity of tryptamine chemistry with the specificity and selectivity of enzymatic catalysis and helps provide access to an important drug at potentially reasonable cost., The benefits of bulk: Future use of psilocybin as a medication will entail increased demand. We present a gram‐scale synthetic/biocatalytic approach in which the mushroom kinase PsiK replaces tedious chemical phosphorylation. A pilot‐scale protocol to make three‐digit milligram amounts of pure and active recombinant PsiK available is also described.

Light mediates plant growth through diverse mechanisms and signaling networks including plant growth regulators (PGRs). We hypothesized that a novel class of PGRs, the indoleamines, are plant signaling molecules that perceive changes in light composition and initiate a cascade of metabolic responses. We used three Scutellaria model species (skullcap): S. lateriflora, S. galericulata and S. racemosa that produce high levels of melatonin and serotonin to investigate this hypothesis. Axenic Scutellaria cultures were exposed to red, blue, green or full spectrum white light spectra provided by light emitting diode (LED) lighting systems, or daylight fluorescent bulbs. Melatonin (MEL), serotonin (5HT), abscisic acid (ABA), auxin (IAA), and jasmonic acid (JA), were quantified by liquid chromatography with tandem mass spectrometry. Melatonin was detected consistently in plants grown under blue light in all species of Scutellaria. In S. galericulata, significant quantities of ABA were detected in plants grown under white light but not detected in plants grown under other light spectra. In timeline studies of S. racemosa plants exposed to limited red or blue light spectra had significantly reduced levels of tryptamine (TRM), 5HT and MEL in the shoots initially but melatonin was detected after 12 hours and quantifiable amounts of 5HT were detected after 7 days. Supplementation of the culture medium with MEL or 5HT did not change the pattern of MEL in blue light grown cultures but did change patterns of 5HT accumulation. 5HT was highest in plants grown under red light immediately after culture and decreased over 7 days. These data indicate that the relative amounts of MEL and 5HT are responsive to light spectra and redirect metabolic resources to enable plant adaptations to changing environments.

A general synthetic method was developed to access known tryptamine natural products present in psilocybin-producing mushrooms. In vitro and in vivo experiments were then conducted to inform speculations on the psychoactive properties, or lack thereof, of the natural products. In animal models, psychedelic activity by baeocystin alone was not evident using the mouse head twitch response assay, despite its putative dephosphorylated metabolite, norpsilocin, possessing potent agonist activity at the 5-HT2A receptor.

Spiro[indoline-3,4'-piperidine] is a significant structural scaffold in numerous polycyclic indole alkaloids with a variety of bioactivities. In this study, a synthetic strategy was developed to access spiro[indoline-3,4'-pyridin]-2-yl carbamate via an AgOTf/PPh3-catalyzed tandem cyclization of tryptamine-ynesulfonamides. The unique feature of this strategy is the efficient intermolecular capturing of the in situ generated spiroindoleninium intermediates with carbamates, leading to the diastereoselective syntheses of spiro[indoline-3,4'-pyridin]-2-yl carbamate derivatives. A broad scope of this cyclization was demonstrated by a variety of tryptamine-ynesulfonamide substrates and several carbamates. A plausible mechanism of this reaction was proposed.

Nothapodytes foetida, an endangered tree of Indian origin, is a major source of the anti-cancer monoterpenoid indole alkaloid, camptothecin (CPT). Strictosidine synthase (STR) condenses tryptamine and secologanin to form strictosidine, a universal precursor of terpenoid indole alkaloids including CPT. We cloned full-length str cDNA with an open reading frame of 1059 bp from N. foetida (Nfstr) using a homology-based approach. Different tissues of N. foetida from in vitro grown cultures, as well as a mature tree, showed expression of STR, confirming the constitutive nature of the gene. In vitro tissues showed a positive correlation between STR expression and the CPT content, but tissues from wild-type mature plants did not show a similar pattern. Transgenic Ophiorrhiza rugosa plants overexpressing Nfstr showed 1.9-fold higher CPT than non-transformed plants. The results indicated that overexpression of Nfstr in target plants could improve the levels of CPT and may provide an alternative and sustainable source of camptothecin. We report the full-length sequence and expression analysis of strictosidine synthase cDNA from Nothapodytes foetida (Nfstr). Further, the overexpression of Nfstr in Ophiorrhiza resulted in twofold enhancement in camptothecin levels.

Indigestible dietary protein fermentation products have been suggested to negatively influence broiler performance due to their impact on health and digestive tract morphology. This study evaluated the digestive tract morphology and caecal protein fermentation metabolites of broiler fed 3 dietary protein levels (24%, 26% and 28%) with low or high indigestible protein (LIP, HIP). Two completely randomized 3 × 2 factorial trials were conducted with protein level (PL) and indigestible protein (IDP) as the main factors. In both trials, birds received six diets (24-LIP, 24-HIP, 26-LIP, 26-HIP, 28-LIP and 28 HIP) formulated with no medication. On day 5, trial 1 birds were vaccinated with Coccivac-B52, while trial 2 received no vaccine. Tissue and caecal samples were collected and caecal contents analysed for fermentation metabolites. Differences were considered significant when p ≤ .05. The LIP treatment caecal content in trial 1 at 14 days had greater histamine, agmatine and cadaverine levels, while HIP diets resulted in increased serotonin, tryptamine and spermidine. Histamine, serotonin and tryptamine at day 28 were not affected by IDP, and ammonia was not affected by treatments at day 14 or day 28. At day 14, HIP birds had lower total short-chain fatty acids, higher caecal pH and heavier pancreas, proventriculus, gizzard, jejunum and ileum weights. The same effects of IDP found in trial 1 were observed for histamine, agmatine, cadaverine, serotonin, tryptamine and spermidine at day 21 in trial 2. Trial 2 had a PL-by-IDP interaction influencing tyramine, spermidine (28-LIP > 24-LIP) and spermine with values increasing with PL for LIP diets and remaining constant for HIP diets. An interaction between PL and IDP was found for ammonia level and was similar to interactions for biogenic amines. In conclusion, dietary PL and IDP influence broiler caecal protein fermentation metabolites and those effects varied with coccidiosis vaccination and rearing environment.

N-(2-(1H-Indol-3-yl)ethyl)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)propanamide was prepared by a reaction between tryptamine and flurbiprofen, applying N,N’-dicyclohexylcarbodiimide, as a coupling agent. The obtained new amide has a fragment similar to Brequinar, a compound used in SARS-CoV-2 treatment trials. The newly synthesized compound was fully analyzed and characterized via 1H, 13C-NMR, UV, IR, and mass spectral data.

Background: 5-Methoxy- N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring, short-acting psychedelic tryptamine, produced by a variety of plant and animal species. Plants containing 5-MeO-DMT have been used throughout history for ritual and spiritual purposes. The aim of this article is to review the available literature about 5-MeO-DMT and inform subsequent clinical development. Methods: We searched PubMed database for articles about 5-MeO-DMT. Search results were cross-checked against earlier reviews and reference lists were hand searched. Findings were synthesised using a narrative synthesis approach. This review covers the pharmacology, chemistry and metabolism of 5-MeO-DMT, as well epidemiological studies, and reported adverse and beneficial effects. Results: 5-MeO-DMT is serotonergic agonist, with highest affinity for 5-HT1A receptors. It was studied in a variety of animal models, but clinical studies with humans are lacking. Epidemiological studies indicate that, like other psychedelics, 5-MeO-DMT induces profound alterations in consciousness (including mystical experiences), with potential beneficial long-term effects on mental health and well-being. Conclusion: 5-MeO-DMT is a potentially useful addition to the psychedelic pharmacopoeia because of its short duration of action, relative lack of visual effects and putatively higher rates of ego-dissolution and mystical experiences. We conclude that further clinical exploration is warranted, using similar precautions as with other classic psychedelics.

Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using “clickable” fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Copper(I)-catalyzed azide-alkyne cycloaddition allowed to effectively synthesize a series of final heterodimers, and modeling and kinetic studies confirmed their ability to bind to both CAS and PAS. A potent acetylcholinesterase inhibitor with IC50 = 18 nM (compound 23g) was discovered. A target-guided approach to link fragments by the enzyme itself was tested using butyrylcholinesterase.

Research Areas: Environmental Sciences & Ecology ; Public, Environmental & Occupational Health : Dry-cured sausages are traditional in Mediterranean countries, and Paio do Alentejo (PA) is one of the most popular in South Portugal. The aim of the present work was to evaluate the effect of combined starters on the safety and quality of PA preserving its sensory quality. Physicochemical parameters, namely pH and water activity (aW), microbiological parameters, biogenic amines, color, texture, and sensory attributes were assessed. Three starter cultures were used, namely Staphylococcus equorum S2M7 and Lactobacillus sakei CV3C2, both separate and combined with the 2RB4 yeast strain at a concentration of 106 cfu/g. Dextrose 0.25% was added to the meat batter. Starters had a significant effect on the reduction of aW values (0.845 to 0.823). The treatment with L. sakei as well as the co-inoculation of L. sakei with S. equorum effectively reduced the L. monocytogenes counts to undetectable levels. Sausages co-inoculated with S. equorum S2M7/L. sakei CV3C2 showed a significant reduction in the content of vasoactive amines, namely tryptamine (26.21 to 15.70) and β-phenylethylamine (4.80 to 3.69). Regarding texture, control PA showed higher hardness values, and the starters promoted the cohesiveness of the batter while reducing chewiness. The studied starters did not compromise the sensory characteristics of PA. info:eu-repo/semantics/publishedVersion

Zhiqi Shi,1,2 Shugang Pan,3,4 Luolin Wang,5 Sha Li2 1School of Pharmacy, Changzhou Institute of Industry and Technology, Changzhou, Jiangsu, People’s Republic of China; 2Longsha Medical Research Institute, Wuxi Hospital of Traditional Chinese Medicine, Wuxi, Jiangsu, People’s Republic of China; 3School of Pharmacy, Changzhou Institute of Technology, Changzhou, 213022, People’s Republic of China; 4Key Laboratory for Soft Chemistry and Functional Materials of Ministry Education, Nanjing University of Science and Technology, Nanjing, People’s Republic of China; 5Department of Pharmacy, Guangdong Provincial Institute of Traditional Chinese Medicine, Guangzhou, People’s Republic of ChinaCorrespondence: Zhiqi ShiSchool of Pharmacy, Changzhou Institute of Industry and Technology, No. 28#, Mingxin Road, Changzhou, Jiangsu Province, 213164, People’s Republic of ChinaTel +86 519-86335118Email shi_mars@foxmail.comSha LiLongsha Medical Research Institute, Wuxi Hospital of Traditional Chinese Medicine, No. 8#, Zhongnan Road, Wuxi, Jiangsu Province, 214071, People’s Republic of ChinaTel +86 510-88859999Email sl0426@foxmail.comIntroduction: Oleanolic acid (OA) has been shown to be useful for the treatment of mental disorders.Methods: In this study, we investigated the effects of OA in animal models of spontaneous withdrawal and naloxone-precipitated withdrawal and evaluated the effects of OA on the acquisition, extinction, and reinstatement of morphine-induced conditioned place preference (CPP).Results: OA significantly improved symptoms of withdrawal, and significantly reduced the acquisition and reinstatement of morphine-induced conditioned place preference. Moreover, OA significantly reduced the serum content of 5-hydroxy tryptamine (5-HT) and dopamine (DA) in a dose-dependent manner, and reduced norepinephrine (NE) and 5-HT content in the frontal cortex (PFC), while significantly increasing endorphin content in rats. OA also significantly reduced serum DA content in mice.Conclusion: These results indicate that OA can improve the withdrawal symptoms of rats and mice by regulating the DA system and suggest that OA may be useful in treatment of morphine addiction.Keywords: OA, withdrawal, morphine-induced, rats, mice

The current coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), highlights major gaps in our knowledge on the prevention control and cross-species transmission mechanisms of animal coronaviruses. Transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and porcine delta coronavirus (PDCoV) are three common swine coronaviruses and have similar clinical features. In the absence of effective treatments, they have led to significant economic losses in the swine industry worldwide. We reported that indoles exerted potent activity against swine coronaviruses, the molecules used included melatonin, indole, tryptamine, and L-tryptophan. Herein, we did further systematic studies with melatonin, a ubiquitous and versatile molecule, and found it inhibited TGEV, PEDV, and PDCoV infection in PK-15, Vero, or LLC-PK1 cells by reducing viral entry and replication, respectively. Collectively, we provide the molecular basis for the development of new treatments based on the ability of indoles to control TGEV, PEDV, and PDCoV infection and spread.

Chemotherapy fails to achieve an ideal gliomas therapy due to the limited delivery of chemotherapeutics across the blood brain barrier (BBB), difficult accumulation of drugs in the gliomas area, and off-target toxicity. Herein, the pH-triggered small molecule nano-prodrugs (Try-CA-NPs) emulsified from hydrophobic tryptamine (Try)-cinnamaldehyde (CA) twin drug were successfully prepared through a facile method. Try-CA-NPs exhibited long-term storage and circulation stability. Furthermore, liposoluble Try-CA-NPs could easily cross BBB and efficiently accumulate in brain, selectively target to gliomas cells via Try-mediated cellular uptake, and enhance cytotoxicity through intracellular pH-triggered endosomal escape and efficient drug release, and synergistic effect between CA and Try, therefore achieving the complete destruction of SH-SY5Y multicellular spheroids (MCs). Thus, the pH-triggered small molecule nano-prodrugs emulsified from Try-CA twin drug have the great potential for clinically targeted synergistic glioma therapy.

Two hydroxybenzoyl amines, 4-hydroxybenzoyl tyramine (4-HBT) and N-2-hydroxybenzoyl tryptamine (2-HBT), were synthesized using Escherichia coli. While 4-HBT was reported to demonstrate anti-atherosclerotic activity, 2-HBT showed anticonvulsant and antinociceptive activities. We introduced genes chorismate pyruvate-lyase (ubiC), tyrosine decarboxylase (TyDC), isochorismate synthase (entC), isochorismate pyruvate lyase (pchB), and tryptophan decarboxylase (TDC) for each substrate, 4-hydroxybenzoic acid (4-HBA), tyramine, 2-hydroxybenzoic acid (2-HBA), and tryptamine, respectively, in E. coli. Genes for CoA ligase (hbad) and amide formation (CaSHT and OsHCT) were also introduced to form hydroxybenzoic acid and amine conjugates. In addition, we engineered E. coli to provide increased substrates. These approaches led to the yield of 259.3 mg/l 4-HBT and 227.2 mg/l 2-HBT and could be applied to synthesize diverse bioactive hydroxybenzoyl amine conjugates.

Herbaceous peony (Paeonia lactiflora Pall.) is known as the king of herbaceous flowers. Drought stress seriously restricts P. lactiflora growth and reduces its ornamental value, but little is known about its underlying mechanism. In this study, one tryptophan decarboxylase gene (TDC), which is the first enzyme gene for melatonin biosynthesis, was obtained, and its expression level was found to be positively related to melatonin production during drought stress. In P. lactiflora, the first TDC that was isolated was comprised of 1849 bp with no intron, and was designated as PlTDC (KY765554). It encoded a 502-amino acid protein with a molecular weight of 56 kDa, which was localized in the cytoplasm of cells and catalyzed the reaction converting tryptophan into tryptamine. When PlTDC was transferred into tobacco, the transgenic plants produced approximately 1.67-fold higher levels of melatonin than that of wild-type control. Moreover, the transgenic plants had enhanced tolerance to drought and salt stresses, potentially due to the reduction in hydrogen peroxide (H2O2) and superoxide anion free radical (O2 −) accumulation. In addition, the enhanced H2O2 and O2 − scavenging under drought stress led to decreased cell membrane damage, increased potential photosynthetic capacity, and delayed plant senescence. RNA-Seq data correlated well with the protective role of melatonine because it was found an increase of gene expression involved in the oxidation-reduction process and photosynthesis. These results together suggested that PlTDC was a key factor in increasing melatonin production, to confer drought and salt stress tolerance in P. lactiflora.

Catharanthus roseus is a well-known herb with great pharmaceutical value for being the only source of natural antineoplastic drugs vinblastine and vincristine. The terpenoid indole alkaloids (TIAs) biosynthetic pathway responsible for the production of these antineoplastic drug molecules is under a strict spatiotemporal regulation that requires five different cellular as well as at least four intracellular compartmentations for its completion. Therefore, several efforts were made to investigate the cell and tissue cultures of Catharanthus roseus to establish as an alternative source of TIAs production. Cell suspension, hairy roots and callus cultures of Catharanthus roseus do not provide the required cellular complexity for the completion of entire TIAs pathway, therefore, failed to produce vinblastine and vincristine. However, the multiple shoot cultures do provide the required cellular complexity to complete the entire TIAs pathway. Therefore, in the present study, the multiple shoot cultures along with callus cultures were subjected to the abiotic elicitors and TIAs pathway precursors feeding for the first time to chase the effect of these abiotic elicitors and pathway precursors on the production of major TIAs of Catharanthus roseus. The multiple shoot cultures treated with TIAs pathway precursor tryptamine 300 mg/L accumulated highest vinblastine content (0.0277% dry wt) followed by tryptophan feeding at 300 mg/L (0.0180% dry wt) and 500 mg/L (0.0175% dry wt) whereas, callus cultures failed to produce vinblastine.

Novel Schiff bases such as N-cyclohexylidene-2(1H-indol-3-yl) ethanamine [TCH], 2-(1H-indol-3-yl)-N-((1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)ethanamine [TC], 2-(1H-indol-3-yl)-N-(1-phenylethylidene)ethanamine [TAP] were prepared by the condensation reaction of tryptamine with cyclo hexanone , camphor and aceto phenone. The imines were characterised by UV-Visible, FT-IR and H1NMR spectral data. All the three Schiff bases were screened for antibacterial (staphylococcus aureus, Bacillus substilis, salmoneila typhi and Proteus Vulgaris) and antifungal (candida alibicans, Aspergilus niger) activities by disc diffusion method. The results indicate that all imines exhibit significant antimicrobial activity.

A series of tryptamine salicylic acid derivatives were synthesized and their antiproliferative activity against MGC-803, MCF-7, HepG2, A549 and HeLa cell lines was evaluated. The structure–activity relationship (SAR) study revealed that different substitutions of the C5 and C3′–C5′ positions have certain effects on the anti-proliferation activity. The growth assay revealed that N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide (E20) showed the most potent and broad-spectrum anticancer inhibition of all the cell lines evaluated, and was only more potent than 5-Fu for the gastric cancer cell line. Preliminary studies indicated that compound E20 could inhibit colony formation and migration of MGC-803 cells. The flow cytometry (FCM) results showed that compound E20 arrested the cell cycle in the G2/M phase and induced apoptosis of MGC-803 cells in a concentration-dependent manner. In addition, the western blot results showed that E20 can down-regulate the expression of hexokinase 2. Our studies suggest that the framework of N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide may be consider as a new type of chemical for designing effective anti-cancer drugs targeting gastric cancer cells.

A facile and efficient route to synthesize N-heterocyclic fused tryptamine-piperazine-2,5-dione conjugates was developed via a post-Ugi cascade reaction. The targeted compounds were prepared by means of a mild reaction and simple operation procedure, which could be applied to a broad scope of starting materials. Compound 6h was demonstrated to induce significant growth inhibition of AsPC-1 and SW1990 human pancreatic cancer cell lines (IC50 = 6 ± 0.85 μM). Our protocol allows for the construction of a structurally diverse compound library and paves a new avenue for the discovery of pancreatic cancer drug candidates.

Psilocin (1) is the dephosphorylated and psychotropic metabolite of the mushroom natural product psilocybin. Oxidation of the phenolic hydroxy group at the C‐4 position of 1 results in formation of oligomeric indoloquinoid chromophores responsible for the iconic blueing of bruised psilocybin‐producing mushrooms. Based on previous NMR experiments, the hypothesis included that the 5,5’‐coupled quinone dimer of 1 was the primary product responsible for the blue color. To test this hypothesis, ring‐methylated 1 derivatives were synthesized to provide stable analogs of 1 dimers that could be completely characterized. The chemically oxidized derivatives were spectroscopically analyzed and compared to computationally derived absorbance spectra. Experimental evidence did not support the original hypothesis. Rather, the blue color was shown to stem from the quinoid 7,7’‐coupled dimer of 1., Self‐made color frenzy: Psilocin oxidation causes the iconic blueing of Psilocybe “magic” mushrooms. To prevent oligomerization, but allow for dimerization, 5‐ and 7‐methylated psilocin monomers were synthesized. Chemical oxidation enabled spectroscopic chromophore investigation of the dimeric gateway compounds and comparison to computationally derived absorption spectra. The 7,7’‐coupled quinoid psilocyl dimer was identified as major initial blue product, while the 5,5’‐coupled dimer contributes a greenish tint.

COX-2 and STAT3 are two key culprits in the glioma microenvironment. Herein, to inhibit COX-2 and block STAT3 signaling, we disclosed 27 N-anthraniloyl tryptamine compounds based on the combination of melatonin derivatives and N-substituted anthranilic acid derivatives. Among them, NP16 showed the best antiproliferative activity and moderate COX-2 inhibition. Of note, NP16 decreased the level of p-JAK2 and p-STAT3, and blocked the nuclear translocation of STAT3 in GBM cell lines. Moreover, NP16 downregulated the MMP-9 expression of BV2 cells in a co-culture system of BV2 and C6 glioma cells, abrogated the proliferative/invasive/migratory abilities of GBM cells, induced apoptosis by ROS and the Bcl-2-regulated apoptotic pathway, and induced obvious G2/M arrest in glioma cells in vitro. Furthermore, NP16 displayed favorable pharmacokinetic profiles covering long half-life (11.43 ± 0.43 h) and high blood-brain barrier permeability. Finally, NP16 effectively inhibited tumor growth, promoted the survival rate, increased the expression of E-cadherin and reduced overproduction of PGE2, MMP-9, VEGF-A and the level of p-STAT3 in tumor tissue, and improved the anxiety-like behavior in C6 glioma model. All these evidences demonstrated N-anthraniloyl tryptamine derivatives as multifunctional anti-glioma agents with high potency could drain the swamp to beat glioma.

Background: N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings. Aims: Our primary aim was to study the acute effects of inhaled N,N-dimethyltryptamine in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. “set“ and “setting“), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming N,N-dimethyltryptamine in familiar and comfortable settings. Methods: We combined state-of-the-art wireless electroencephalography with psychometric questionnaires to study the neural and subjective effects of naturalistic N,N-dimethyltryptamine use in 35 healthy and experienced participants. Results: We observed that N,N-dimethyltryptamine significantly decreased the power of alpha (8–12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1–4 Hz) and gamma (30–40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of some features of mystical-type experiences. N,N-dimethyltryptamine also increased global synchrony and metastability in the gamma band while decreasing those measures in the alpha band. Conclusions: Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time the results suggest potential electroencephalography markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

Cloning techniques are used to improve agronomical traits and answer to the demand for fine chocolate. The objective of this study was to predict the concentrations of bioactive amines, phenolic compounds, and the antioxidant potential of dark monoclonal chocolate from nine fine cocoa varieties by FTIR analysis and conventional techniques. Total phenolic compounds, bioactive amines and antioxidant activity varied significantly among chocolates. The antioxidant activity was also affected by the analytical method (DPPH vs. Rancimat). Chemometric models based on FTIR data provided satisfactory predictions of the concentrations of the amines: spermidine (R2 = 0.92; RMSEP = 0.39; RMSEC = 0.21), tryptamine (R2 = 0.92; RMSEP = 0.41; RMSEC = 0.20), cadaverine (R2 = 0.82; RMSEP = 1.58; RMSEC = 0.75) and tyramine (R2 = 0.87; RMSEP = 1.87; RMSEC = 0.68); as well as phenolic compounds and antioxidant activity by Rancimat® (R2 = 0.98; RMSEP = 0.32; RMSEC = 0.21) and DPPH (R2 = 0.97; RMSEP = 4.05; RMSEC = 1.66). The wavenumbers of amines vibrations are among those that most affected antioxidant prediction models, confirming the contribution of amines to the antioxidant activity of chocolates.

Melatonin (N-acetyl-5-methoxytryptamine), a well-known animal hormone, is involved in several biological processes including circadian rhythm and the regulation of abiotic stress. A systematic understanding of the circadian regulation of melatonin biosynthesis-related genes has not been achieved in rice. In this study, key genes for all of the enzymes in the melatonin biosynthetic pathway that showed a peak of expression at night were identified by microarray data analysis and confirmed by qRT&ndash, PCR analysis. We further examined the expression patterns of the four genes under drought, salt, and cold stresses. The results showed that abiotic stresses, such as drought, salt, and cold, affected the expression patterns of melatonin biosynthetic genes. In addition, the circadian expression patterns of tryptophan decarboxylase (TDC), tryptamine 5-hydroxylase (T5H), and serotonin N-acetyltransferase (SNAT) genes in wild-type (WT) plants was damaged by the drought treatment under light and dark conditions. Conversely, N-acetylserotonin O-methyltransferase (ASMT) retained the circadian rhythm. The expression of ASMT was down-regulated by the rice gigantea (OsGI) mutation, suggesting the involvement of the melatonin biosynthetic pathway in the OsGI-mediated circadian regulation pathway. Taken together, our results provide clues to explain the relationship between circadian rhythms and abiotic stresses in the process of melatonin biosynthesis in rice.

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.