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Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer’s disease (AD) treatment due to a growing understanding of AD’s complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.

A novel class of benzyl-free and benzyl-substituted carbamylated tryptamine derivatives (CDTs) was designed and synthesized to serve as effective building blocks for the development of novel multi-target directed ligands (MTDLs) for the treatment of neurological disorders linked to cholinesterase (ChE) activity. The majority of them endowed butyrylcholinesterase (BuChE) with more substantial inhibition potency than acetylcholinesterase (AChE), according to the full study of ChE inhibition. Particularly, hybrids with dibenzyl groups ( 2b-2f , 2j , 2o , and 2q ) showed weak or no neuronal toxicity and hepatotoxicity and single-digit nanomolar inhibitory effects against BuChE. Through molecular docking and kinetic analyses, the potential mechanism of action on BuChE was first investigated. In vitro H 2 O 2 -induced HT-22 cells assay demonstrated the favorable neuroprotective potency of 2g , 2h , 2j , 2m , 2o , and 2p . Besides, 2g , 2h , 2j , 2m , 2o , and 2p endowed good antioxidant activities and COX-2 inhibitory effects. This study suggested that this series of hybrids can be applied to treat various ChE-associated neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as promising building blocks for further structure modification to develop efficient MTDLs.

Twenty-four new hybrid Pyrrole-tryptamines compounds were synthesized and thoroughly characterized using various techniques such as FT-IR, 1 H NMR, 13 C NMR, and LC-MS. An evaluation of each compound was conducted based on criteria including their PASS, BBB, ADME, pharmacophore model, and bioactive score. Antibacterial testing of all derivatives indicated that compound 5j exhibited strong activity against MRSA. Investigations into membrane damage, supported by SEM images, cellular content leakage, potassium efflux, and changes in lipid profiles, confirmed the anti-MRSA properties of compound 5j. In an in silico molecular docking analysis, compound 5j achieved a binding score of − 10.02 against the MRSA protein 6FTB, while streptomycin scored − 10.25. Additionally, when compared to standard doxorubicin against 3T3L1 cell lines, compound 5j demonstrated a less toxic IC 50 effect of 669.80 µM on normal cell lines. These findings warrant further research on compound 5j for the potential development of a medication to treat MRSA infections.

Oxidative stress is one of the main causative factors for pathogenesis of numerous disorders including psychological and neurodegenerative diseases (Alzheimer’s disease and Parkinsonism). Amyloid aggregates induced oxidative stress is involved in disfunction and degeneration of brain cells in Alzheimer’s disease. Antioxidants are important natural or synthetic molecules having tendency to curb free radicals and discontinuing their chain reactions prior to the damage of essential biomolecules. Drugs possessing antioxidant activity are being extensively anticipated for developing novel therapeutic agents in numerous pathological conditions accompanying oxidative stress like AD. In this study twelve tryptamine derivatives were synthesized and investigated for antioxidant, fibril inhibition and disaggregation potential. In vitro antioxidant potential of the derivatives was examined by using DPPH (2,2‑diphenyl‑1‑picrylhydrazyl) assay and revealed that SR10, SR14, SR23 and SR42 displayed better antioxidant activity (IC50 in the range of 0.75±0.05µM-14.43±0.77µM) than the standard ascorbic acid (IC50 =15.83±0.88µM). In vitro amyloid fibril inhibition and disaggregation assay was carried out by using HEWL (Hen egg white lysozyme) presenting moderate to high inhibition/disaggregation activities. Molecular dockingassessment recognized themode of bindingswithin active site of human antioxidant enzyme peroxiredoxin (PDB ID: 3MNG). These tryptamine derivatives with potential antioxidant and inhibition/disaggregation activitieswill be beneficialto develop and designdrug molecules forneurodegenerative disorders.

Background Panaeolus foenisecii (Pers.) R. Maire, commonly known as the brown hay or lawnmower’s mushroom, is a small saprotrophic species common in temperate regions of Europe and North America, colonizing nutrient-rich lawns, meadows, and parklands. Although it belongs to a genus that includes psychoactive mushrooms, recent studies classify it as non-hallucinogenic. Morphologically, it is characterized by a hygrophanous brown cap, mottled dark gills, and ellipsoid warty spores, making it a distinctive yet often overlooked member of urban and rural grassland ecosystems. Main Body As a litter-decomposing fungus, Panaeolus foenisecii contributes to nutrient recycling and soil fertility and may act as a bioindicator sensitive to soil pH, composition, and moisture. Chemical analyses have identified serotonin and 5-hydroxytryptophan among its metabolites, compounds associated with antioxidant and anti-inflammatory activity. Their concentrations vary with environmental factors such as temperature, rainfall, and soil mineral content, indicating ecophysiological plasticity. Toxicological data show only mild and transient gastrointestinal symptoms after accidental ingestion in humans or animals, suggesting minimal health risk. Despite lacking culinary or recreational use, the occurrence of bioactive indole derivatives underscores its potential ecological and pharmacological relevance. Conclusion Panaeolus foenisecii illustrates the ecological and biochemical diversity within the Panaeolus genus and highlights the need for further investigation of non-hallucinogenic species. Its metabolic profile and environmental sensitivity make it a valuable model for studying fungal adaptation and the ecological significance of indole-based metabolites .

It is unclear whether hallucinogenic tryptamine derivatives namely N , N -dimethyl-tryptamine (DMT) and 5-methoxy- N , N -dimethyl-tryptamine (5-MeO-DMT) exert positive inotropic effects in the human heart. Therefore, we measured the inotropic effects of these drugs in isolated left and right atrial preparations of mice that overexpress human 5-HT 4 receptors (5-HT 4 -TG) and preparations from wild type mice (WT). Moreover, we measured force of contraction in isolated right atrial preparations from adult patients, obtained in the process of open heart surgery due to severe coronary heart disease. DMT and 5-MeO-DMT augmented the force of contraction in isolated paced (1 Hz) left atrial preparations from 5-HT 4 -TG and raised the spontaneous beating rate of right atrial preparations from 5-HT 4 -TG. The drugs elevated force of contraction in paced (1 Hz) human right atrial muscle preparations. The maximum inotropic effects of DMT and 5-MeO-DMT were smaller at 10 µM (about 65%) than that of 1 µM 5-HT on the left atria from 5-HT 4 -TG. The maximum increase in the beating rate due to DMT and 5-MeO-DMT amounted 40 ± 5% of the effect of 5-HT on right atrial preparations from 5-HT 4 -TG ( n  = 5–6). DMT and 5-MeO-DMT were inactive in WT. The potency of 5-MeO-DMT to increase force of contraction could be increased by pre-treatment of human atrial preparations by the phosphodiesterase inhibitor cilostamide (1 µM). 5-MeO-DMT increased the phosphorylation state of phospholamban at serine 16 in isolated left atrial muscle strips of 5-HT 4 -TG. In summary, DMT and 5-MeO-DMT acted as partial agonists on human 5-HT 4 receptors.

PurposeTo 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.MethodsThe 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.ResultsSix 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.ConclusionsThe continuous provisional monitoring of newly detected compounds in illicit products will largely prevent the distribution of these products.

Nine isotopomers of tryptamine and its halogen derivatives, labeled with deuterium, tritium in side chain, i.e., [(1R)-2H]-, [(1R)-3H]-, 5-F-[(1R)-2H]-, 5-F-[(1R)-3H]-, 5-Br-[(1R)-2H]-, double labeled [(1R)-2H/3H]-, 5-F-[(1R)-2H/3H]-, and ring labeled [4-2H]-, and [5-2H]-tryptamine, were obtained by enzymatic decarboxylation of l-Trp and its appropriate derivatives in deuteriated or tritiated media, respectively. Intermediates: [5′-2H]-l-Trp used for further decarboxylation was synthesized by enzymatic coupling of [5-2H]-indole with S-methyl-l-cysteine, and [4′-2H]-l-Trp was obtained by isotope exchange 1H/2H of the authentic l-Trp dissolved in heavy water induced by UV-irradiation. Doubly labeled [(1R)-2H/3H]- and 5-F-[(1R)-2H/3H]-tryptamine were obtain by decarboxylation of l-Trp or [5′-F]-l-Trp carried out in 2H3HO incubation medium.

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring psychedelic tryptamine. Plants containing 5-MeO-DMT have been used throughout history, and in recent years both synthetic and toad-derived 5-MeO-DMT use is being increasingly reported in naturalistic settings as well as clinical research. However, its subjective effects are not well characterised, and no qualitative research studies have been published to date. In this study, 32 psychedelic-naïve healthy participants from a double-blind, randomised, placebo-controlled, phase 1 trial of the escalating doses of a proprietary formulation of intranasal 5-MeO-DMT (BPL-003) were interviewed using the microphenomenology method shortly after dosing sessions. Microphenomenology is a qualitative research method well-suited to elucidating how subjective effects of this short-acting psychedelic unfold over time. Detailed qualitative and quantitative analysis of interview transcripts revealed a generic time-course of subjective effects, with rapid onset peaking at 8–15 min and gradual return to baseline over 45–60 min. The overall intensity of effects increased with dose and the doses tested were generally well tolerated. 5-MeO-DMT has a distinctive profile of subjective effects relative to published reports of other psychedelics, with a short duration of action, relative lack of visual effects, strong emotional or bodily experiences and the potential to elicit therapeutically relevant content, such as emotional breakthroughs and personal insights. These findings inform therapeutic applications, participant preparation, and future research on 5-MeO-DMT.

In previous studies, we have isolated several marine indole alkaloids and evaluated them in the forced swim test (FST) and locomotor activity test, revealing their potential as antidepressant and sedative drug leads. Amongst the reported metabolites to display such activities was 5-bromo-N,N-dimethyltryptamine. Owing to the importance of the judicious introduction of halogens into drug candidates, we synthesized two series built on a 2-(1H-indol-3-yl)-N,N-dimethylethanamine scaffold with different halogen substitutions. The synthesized compounds were evaluated for their in vitro and in vivo antidepressant and sedative activities using the mouse forced swim and locomotor activity tests. Receptor binding studies of these compounds to serotonin (5-HT) receptors were conducted. Amongst the prepared compounds, 2-(1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (1a), 2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (1d), 2-(1H-indol-3-yl)-N,N-dimethylethanamine (2a), 2-(5-chloro-1H-indol-3-yl)-N,N-dimethylethanamine (2c), 2-(5-bromo-1H-indol-3-yl)-N,N-dimethylethanamine (2d), and 2-(5-iodo-1H-indol-3-yl)-N,N-dimethylethanamine (2e) have been shown to possess significant antidepressant-like action, while compounds 2c, 2d, and 2e exhibited potent sedative activity. Compounds 2a, 2c, 2d, and 2e showed nanomolar affinities to serotonin receptors 5-HT1A and 5-HT7. The in vitro data indicates that the antidepressant action exerted by these compounds in vivo is mediated, at least in part, via interaction with serotonin receptors. The data presented here shows the valuable role that bromine plays in providing novel chemical space and electrostatic interactions. Bromine is ubiquitous in the marine environment and a common element of marine natural products.