Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease recognized as the most common form of dementia among elderly people. Due to the fact that the exact pathogenesis of AD still remains to be fully elucidated, the treatment is only symptomatic and available drugs are not able to modify AD progression. Considering the increase in life expectancy worldwide, AD rates are predicted to increase enormously, and thus the search for new AD drugs is urgently needed. Due to their complex nitrogen-containing structures, alkaloids are considered to be promising candidates for use in the treatment of AD. Since the introduction of galanthamine as an antidementia drug in 2001, Amaryllidaceae alkaloids (AAs) and further isoquinoline alkaloids (IAs) have been one of the most studied groups of alkaloids. In the last few years, several compounds of new structure types have been isolated and evaluated for their biological activity connected with AD. The present review aims to comprehensively summarize recent progress on AAs and IAs since 2010 up to June 2021 as potential drugs for the treatment of AD.

• Keywords
• Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, docking study, isoquinoline alkaloids, monoaminooxidase, neuroprotective activity, prolyl oligopeptidase,
• MeSH
• Amaryllidaceae Alkaloids metabolism   MeSH
• Alzheimer Disease metabolism   MeSH
• Amaryllidaceae chemistry   MeSH
• Neurodegenerative Diseases metabolism   MeSH
• Prolyl Oligopeptidases metabolism   MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Amaryllidaceae Alkaloids MeSH
• Prolyl Oligopeptidases MeSH

In recent studies, several alkaloids acting as cholinesterase inhibitors were isolated from Corydalis cava (Papaveraceae). Inhibitory activities of (+)-thalictricavine (1) and (+)-canadine (2) on human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) were evaluated with the Ellman's spectrophotometric method. Molecular modeling was used to inspect the binding mode of compounds into the active site pocket of hAChE. The possible permeability of 1 and 2 through the blood⁻brain barrier (BBB) was predicted by the parallel artificial permeation assay (PAMPA) and logBB calculation. In vitro, 1 and 2 were found to be selective hAChE inhibitors with IC50 values of 0.38 ± 0.05 µM and 0.70 ± 0.07 µM, respectively, but against hBChE were considered inactive (IC50 values > 100 µM). Furthermore, both alkaloids demonstrated a competitive-type pattern of hAChE inhibition and bind, most probably, in the same AChE sub-site as its substrate. In silico docking experiments allowed us to confirm their binding poses into the active center of hAChE. Based on the PAMPA and logBB calculation, 2 is potentially centrally active, but for 1 BBB crossing is limited. In conclusion, 1 and 2 appear as potential lead compounds for the treatment of Alzheimer's disease.

• Keywords
• (+)-canadine, (+)-thalictricavine, blood–brain barrier permeability, cholinesterases, kinetic study, molecular docking,
• MeSH
• Acetylcholinesterase chemistry   drug effects   MeSH
• Alkaloids chemistry   pharmacology   MeSH
• Alzheimer Disease drug therapy   enzymology   MeSH
• Berberine analogs & derivatives   chemistry   pharmacology   MeSH
• Biological Transport drug effects   MeSH
• Butyrylcholinesterase chemistry   drug effects   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Corydalis chemistry   MeSH
• Disaccharides chemistry   pharmacology   MeSH
• Nitro Compounds chemistry   pharmacology   MeSH
• Blood-Brain Barrier drug effects   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Computer Simulation MeSH
• Protein Binding drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Alkaloids MeSH
• Berberine MeSH
• Butyrylcholinesterase MeSH
• canadine MeSH Browser
• Cholinesterase Inhibitors MeSH
• Disaccharides MeSH
• Nitro Compounds MeSH
• thalictricoside MeSH Browser

Alzheimer's disease is an age-related, neurodegenerative disorder, characterized by cognitive impairment and restrictions in activities of daily living. This disease is the most common form of dementia with complex multifactorial pathological mechanisms. Many therapeutic approaches have been proposed. Among them, inhibition of acetylcholinesterase, butyrylcholinesterase, and prolyl oligopeptidase can be beneficial targets in the treatment of Alzheimer's disease. Roots, along with aerial parts of Argemone platyceras, were extracted with ethanol and fractionated on an alumina column using light petrol, chloroform and ethanol. Subsequently, repeated preparative thin-layer chromatography led to the isolation of (+)-laudanosine, protopine, (-)-argemonine, allocryptopine, (-)-platycerine, (-)-munitagine, and (-)-norargemonine belonging to pavine, protopine and benzyltetrahydroisoquinoline structural types. Chemical structures of the isolated alkaloids were elucidated by optical rotation, spectroscopic and spectrometric analysis (NMR, MS), and comparison with literature data. (+)-Laudanosine was isolated from A. platyceras for the first time. Isolated compounds were tested for human blood acetylcholinesterase, human plasma butyrylcholinesterase and recombinant prolyl oligopeptidase inhibitory activity. The alkaloids inhibited the enzymes in a dose-dependent manner. The most active compound (-)-munitagine, a pavine alkaloid, inhibited both acetylcholinesterase and prolyl oligopeptidase with IC50 values of 62.3 ± 5.8 µM and 277.0 ± 31.3 µM, respectively.

• Keywords
• Alzheimer’s disease, Argemone platyceras, acetylcholinesterase, alkaloids, butyrylcholinesterase, prolyl oligopeptidase,
• MeSH
• Alkaloids chemistry   isolation & purification   pharmacology   MeSH
• Alzheimer Disease drug therapy   MeSH
• Argemone chemistry   MeSH
• Butyrylcholinesterase drug effects   MeSH
• Cholinesterases drug effects   MeSH
• Chromatography, Thin Layer methods   MeSH
• Enzyme Assays methods   MeSH
• Inhibitory Concentration 50 MeSH
• Enzyme Inhibitors chemistry   pharmacology   MeSH
• Plant Roots chemistry   MeSH
• Humans MeSH
• Magnetic Resonance Spectroscopy methods   MeSH
• Drug Discovery MeSH
• Prolyl Oligopeptidases MeSH
• Plant Extracts chemistry   MeSH
• Serine Endopeptidases drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alkaloids MeSH
• Butyrylcholinesterase MeSH
• Cholinesterases MeSH
• Enzyme Inhibitors MeSH
• PREPL protein, human MeSH Browser
• Prolyl Oligopeptidases MeSH
• Plant Extracts MeSH
• Serine Endopeptidases MeSH

The California poppy (Eschscholzia californica Cham.) contains a variety of natural compounds including several alkaloids found exclusively in this plant. Because of the sedative, anxiolytic, and analgesic effects, this herb is currently sold in pharmacies in many countries. However, our understanding of these biological effects at the molecular level is still lacking. Alkaloids detected in E. californica could be hypothesized to act at GABAA receptors, which are widely expressed in the brain mainly at the inhibitory interneurons. Electrophysiological studies on a recombinant α 1 β 2 γ 2 GABAA receptor showed no effect of N-methyllaurotetanine at concentrations lower than 30 μM. However, (S)-reticuline behaved as positive allosteric modulator at the α 3, α 5, and α 6 isoforms of GABAA receptors. The depressant properties of aerial parts of E. californica are assigned to chloride-current modulation by (S)-reticuline at the α 3 β 2 γ 2 and α 5 β 2 γ 2 GABAA receptors. Interestingly, α 1, α 3, and α 5 were not significantly affected by (R)-reticuline, 1,2-tetrahydroreticuline, codeine, and morphine-suspected (S)-reticuline metabolites in the rodent brain.

• Publication type
• Journal Article MeSH