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It was found that the diterpene alkaloid songorine administered per os to mice at a dose of 25 μg/kg provides a pronounced anxiolytic effect during elevated plus maze testing comparable to the effect of the benzodiazepine anxiolytic phenazepam. Recording of ultrasonic vocalizations of animals revealed an increase in the number of short high-frequency (50 kHz) signals under the action of songorine and the reference drug, which confirms their anti-anxiety properties. [ABSTRACT FROM AUTHOR]

Cardiac arrhythmias are the most common pathologies of the cardiovascular system. Allapinin® and Allaforte® from “Pharmcenter VILAR” are effective IC-class antiarrhythmic agents. The main component of these drugs is a pharmaceutical substance with INN: lappaconitine hydrobromide, which in addition to lappaconitine hydrobromide itself, contains impurities of other diterpene alkaloids. This work is devoted to a detailed analysis of the alkaloid composition of a new pharmaceutical substance isolated from roots and rhizomes, as well as from the aerial part of plants of the genus Aconite (monkshood, wolfsbane) of the Ranunculaceae family (buttercups) using chromato-mass spectrometry and NMR spectroscopy. In addition, an assessment was made of the quantitative ratios of alkaloids in several samples of pharmaceutical substances isolated from different batches of medicinal plant raw materials.

Diterpenoid alkaloids (DAs) are major pharmacologically active ingredients of Aconitum vilmorinianum, an important medicinal plant. Cytochrome P450 monooxygenases (P450s) are involved in the DA biosynthetic pathway, and the electron transfer reaction of NADPH-cytochrome P450 reductase (CPR) with P450 is the rate-limiting step of the P450 redox reaction. Here, we identified and characterized two homologs of CPR from Aconitum vilmorinianum. The open reading frames of AvCPR1 and AvCPR2 were found to be 2103 and 2100 bp, encoding 700 and 699 amino acid residues, respectively. Phylogenetic analysis characterized both AvCPR1 and AvCPR2 as class II CPRs. Cytochrome c and ferricyanide could be reduced with the recombinant proteins of AvCPR1 and AvCPR2. Both AvCPR1 and AvCPR2 were expressed in the roots, stems, leaves, and flowers of A. vilmorinianum. The expression levels of AvCPR1 and AvCPR2 were significantly increased in response to methyl jasmonate (MeJA) treatment. The yeasts co-expressing AvCPR1/AvCPR2/SmCPR1 and CYP76AH1 all produced ferruginol, indicating that AvCPR1 and AvCPR2 can transfer electrons to CYP76AH1 in the same manner as SmCPR1. Docking analysis confirmed the experimentally deduced functional activities of AvCPR1 and AvCPR2 for FMN, FAD, and NADPH. The functional characterization of AvCPRs will be helpful in disclosing molecular mechanisms relating to the biosynthesis of diterpene alkaloids in A. vilmorinianum. [ABSTRACT FROM AUTHOR]

The genus Aconitum belongs to the family Ranunculaceae, is endowed with more than 350 species on the earth. Medicinally important aconitine type of diterpenoid alkaloids are the characteristic compounds in most of the Aconitum species. The present review endeavored the major research carried out in the field of genetic resource characterization, pharmacological properties, phytochemistry, major factors influencing quantity, biosynthetic pathways and processing methods for recovery of active ingredients, variety improvement, propagation methods, and important metabolite production through cell/organ culture of various Aconitum species. More than 450 derivatives of aconitine-type C19 and C20-diterpenoid alkaloids along with a few other non-alkaloidal compounds, such as phenylpropanoids, flavonoids, terpenoids, and fatty acids, have been identified in the genus. A few Aconitum species and their common diterpenoid alkaloid compounds are also well characterized for analgesic, inflammatory and cytotoxic properties. However, the different isolated compound needs to be validated for supporting other traditional therapeutical uses of the plant species. Aconitine alkaloids shared common biosynthesis pathway, but their diversification mechanism remains unexplored in the genus. Furthermore, the process needs to be developed on secondary metabolite recovery, mass-scale propagation methods, and agro-technologies for maintaining the quality of products. Many species are losing their existence in nature due to over-exploitation or anthropogenic factors; thus, temporal monitoring of the population status in its habitat, and suitable management programs for ascertaining conservation needs to be developed. [ABSTRACT FROM AUTHOR]

This study provides a narrative review of diterpenoid alkaloids (DAs), a family of extremely important natural products found predominantly in some species of Aconitum and Delphinium (Ranunculaceae). DAs have long been a focus of research attention due to their numerous intricate structures and diverse biological activities, especially in the central nervous system (CNS). These alkaloids originate through the amination reaction of tetra or pentacyclic diterpenoids, which are classified into three categories and 46 types based on the number of carbon atoms in the backbone structure and structural differences. The main chemical characteristics of DAs are their heterocyclic systems containing β-aminoethanol, methylamine, or ethylamine functionality. Although the role of tertiary nitrogen in ring A and the polycyclic complex structure are of great importance in drug-receptor affinity, in silico studies have emphasized the role of certain sidechains in C13, C14, and C8. DAs showed antiepileptic effects in preclinical studies mostly through Na+ channels. Aconitine (1) and 3-acetyl aconitine (2) can desensitize Na+ channels after persistent activation. Lappaconitine (3), N-deacetyllapaconitine (4), 6-benzoylheteratisine (5), and 1-benzoylnapelline (6) deactivate these channels. Methyllycaconitine (16), mainly found in Delphinium species, possesses an extreme affinity for the binding sites of α7 nicotinic acetylcholine receptors (nAChR) and contributes to a wide range of neurologic functions and the release of neurotransmitters. Several DAs such as bulleyaconitine A (17), (3), and mesaconitine (8) from Aconitum species have a drastic analgesic effect. Among them, compound 17 has been used in China for decades. Their effect is explained by increasing the release of dynorphin A, activating the inhibitory noradrenergic neurons in the β-adrenergic system, and preventing the transmission of pain messages by inactivating the Na+ channels that have been stressed. Acetylcholinesterase inhibitory, neuroprotective, antidepressant, and anxiolytic activities are other CNS effects that have been investigated for certain DAs. However, despite various CNS effects, recent advances in developing new drugs from DAs were insignificant due to their neurotoxicity. [ABSTRACT FROM AUTHOR]

Diterpenoid alkaloids (DAs) are major pharmacologically active ingredients of Aconitum vilmorinianum, an important medicinal plant. Cytochrome P450 monooxygenases (P450s) are involved in the DA biosynthetic pathway, and the electron transfer reaction of NADPH-cytochrome P450 reductase (CPR) with P450 is the rate-limiting step of the P450 redox reaction. Here, we identified and characterized two homologs of CPR from Aconitum vilmorinianum. The open reading frames of AvCPR1 and AvCPR2 were found to be 2103 and 2100 bp, encoding 700 and 699 amino acid residues, respectively. Phylogenetic analysis characterized both AvCPR1 and AvCPR2 as class II CPRs. Cytochrome c and ferricyanide could be reduced with the recombinant proteins of AvCPR1 and AvCPR2. Both AvCPR1 and AvCPR2 were expressed in the roots, stems, leaves, and flowers of A. vilmorinianum. The expression levels of AvCPR1 and AvCPR2 were significantly increased in response to methyl jasmonate (MeJA) treatment. The yeasts co-expressing AvCPR1/AvCPR2/SmCPR1 and CYP76AH1 all produced ferruginol, indicating that AvCPR1 and AvCPR2 can transfer electrons to CYP76AH1 in the same manner as SmCPR1. Docking analysis confirmed the experimentally deduced functional activities of AvCPR1 and AvCPR2 for FMN, FAD, and NADPH. The functional characterization of AvCPRs will be helpful in disclosing molecular mechanisms relating to the biosynthesis of diterpene alkaloids in A. vilmorinianum.

Songorine (SON) is a diterpenoid alkaloid from Aconitum plants. Preparations of Aconitum roots have been employed in traditional oriental herbal medicine, however, their mechanisms of action are still unclear. Since GABA-receptors are possible brain targets of SON, we investigated which subtypes of GABA-receptors contribute to the effects of SON, and how SON affects anxiety-like trait behavior and psychomotor cognitive performance of rats. First, we investigated the effects of microiontophoretically applied SON alone and combined with GABA-receptor agents picrotoxin and saclofen on neuronal firing activity in various brain areas. Next, putative anxiolytic effects of SON (1.0–3.0 mg/kg) were tested against the GABA-receptor positive allosteric modulator reference compound diazepam (1.0–5.0 mg/kg) in the elevated zero maze (EOM). Furthermore, basic cognitive effects were assessed in a rodent version of the psychomotor vigilance task (PVT). Local application of SON predominantly inhibited the firing activity of neurons. This inhibitory effect of SON was successfully blocked by GABA(A)-receptor antagonist picrotoxin but not by GABA(B)-receptor antagonist saclofen. Similar to GABA(A)-receptor positive allosteric modulator diazepam, SON increased the time spent by animals in the open quadrants of the EOM without any signs of adverse psychomotor and cognitive effects observed in the PVT. We showed that, under in vivo conditions, SON acts as a potent GABA(A)-receptor agonist and effectively decreases anxiety without observable side effects. The present findings facilitate the deeper understanding of the mechanism of action and the widespread pharmacological use of diterpene alkaloids in various CNS indications. [ABSTRACT FROM AUTHOR]

Bullatine G has many biological effects such as anti-inflammatory, anti-anxiety, anti-tumor, anti-arrhythmia and anti-heart failure effect. In order to provide a theoretical basis for the further study and clinical application of bullatine G, this article reviews the biological activity of bullatine G in recent years. [ABSTRACT FROM AUTHOR]

This study provides a narrative review of diterpenoid alkaloids (DAs), a family of extremely important natural products found predominantly in some species of Aconitum and Delphinium (Ranunculaceae). DAs have long been a focus of research attention due to their numerous intricate structures and diverse biological activities, especially in the central nervous system (CNS). These alkaloids originate through the amination reaction of tetra or pentacyclic diterpenoids, which are classified into three categories and 46 types based on the number of carbon atoms in the backbone structure and structural differences. The main chemical characteristics of DAs are their heterocyclic systems containing β-aminoethanol, methylamine, or ethylamine functionality. Although the role of tertiary nitrogen in ring A and the polycyclic complex structure are of great importance in drug-receptor affinity, in silico studies have emphasized the role of certain sidechains in C13, C14, and C8. DAs showed antiepileptic effects in preclinical studies mostly through Na+ channels. Aconitine (1) and 3-acetyl aconitine (2) can desensitize Na+ channels after persistent activation. Lappaconitine (3), N-deacetyllapaconitine (4), 6-benzoylheteratisine (5), and 1-benzoylnapelline (6) deactivate these channels. Methyllycaconitine (16), mainly found in Delphinium species, possesses an extreme affinity for the binding sites of α7 nicotinic acetylcholine receptors (nAChR) and contributes to a wide range of neurologic functions and the release of neurotransmitters. Several DAs such as bulleyaconitine A (17), (3), and mesaconitine (8) from Aconitum species have a drastic analgesic effect. Among them, compound 17 has been used in China for decades. Their effect is explained by increasing the release of dynorphin A, activating the inhibitory noradrenergic neurons in the β-adrenergic system, and preventing the transmission of pain messages by inactivating the Na+ channels that have been stressed. Acetylcholinesterase inhibitory, neuroprotective, antidepressant, and anxiolytic activities are other CNS effects that have been investigated for certain DAs. However, despite various CNS effects, recent advances in developing new drugs from DAs were insignificant due to their neurotoxicity.

Three new diterpene alkaloids, (+)-8-epiagelasine T (1), (+)-10-epiagelasine B (2), and (+)-12-hydroxyagelasidine C (3), along with three known compounds, (+)-ent-agelasine F (4), (+)-agelasine B (5), and (+)-agelasidine C (6), were isolated from the sponge Agelas citrina, collected on the coasts of the Yucatán Peninsula (Mexico). Their chemical structures were elucidated by 1D and 2D NMR spectroscopy, HRESIMS techniques, and a comparison with literature data. Although the synthesis of (+)-ent-agelasine F (4) has been previously reported, this is the first time that it was isolated as a natural product. The evaluation of the antimicrobial activity against the Gram-positive pathogens Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis showed that all of them were active, with (+)-10-epiagelasine B (2) being the most active compound with an MIC in the range of 1–8 µg/mL. On the other hand, the Gram-negative pathogenes Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were also evaluated, and only (+)-agelasine B (5) showed a moderate antibacterial activity with a MIC value of 16 μg/mL. [ABSTRACT FROM AUTHOR]

Rapid characterization of chemical analogues in potentially toxic complex matrix was essential for prevention of accidental poisoning. On the basis of the fragment ions possessed not only the same retention times (RT) but the same drift times (DT) on liquid chromatography-ion mobility-mass spectrometry (LC-IM-MS), an alternating frames (AF)-data independent acquisition (DIA) was utilized for simultaneous detection and rapid match of precursor/product ions with a fast switch of low/high collision energy (CE). A diagnostic ions guided 2D-locating strategy was developed for identification of chemical analogues in potentially toxic herbal medicines using LC-IM-MS. Firstly, the 2D-locations (RT, DT) of diagnostic ions were screened from high-fragment IM-MS frames according to their m/z. Then, the correlated precursor ions were extracted from the complex background interference in low-fragment IM-MS frames based on diagnostic ions' 2D-locations. Finally, the remained ions were characterized using double-bond equivalent analysis combined with MS/MS fragment interpretation. Totally, 236 diterpene alkaloids including eight compounds with potential new esterification types were characterized in processed lateral roots of Aconitum carmichaelii Debx. Moreover, the LC-IM-MS distribution regularities of diterpene alkaloids with various chemical structure types were further investigated and discussed. This study presented an innovative idea for revealing the chemical basis related to the toxicities of potentially poisonous herbal medicines to ensure the medication safety. [ABSTRACT FROM AUTHOR]

Diterpene alkaloids (DAs) have a broad spectrum of pharmacological activities, but exhibiting extremely serious cardiotoxicity to induce arrhythmia, heart arrest, even death. This study aimed to evaluate the cardiotoxicity of three diester diterpene alkaloids (DDAs) including aconitine (AC), mesaconitine (MAC), hypaconitine (HAC) and three monoester diterpene alkaloids (MDAs) including 14-α-benzoylaconine (BAC), 14-α-benzoylmesaconine (BMAC), 14-α-benzoylhypaconine (BHAC) on zebrafish. Firstly, the zebrafish embryos after a 72-hour post fertilization were treated with different doses of AC, MAC, HAC, and BAC, BMAC and BHAC for 2, 10 and 24 h, respectively. The heart rates of the treated embryos were calculated and the morphological images of body, together with heart fluorescence were obtained. Results demonstrated that AC, MAC, and HAC at low doses (15.6 and 31.3 μM) decreased the heart rates and increased them at high doses (62.5, 125, and 250 μM), while BAC, BMAC, and BHAC decreased the heart rates in the dose range of 31.3–250 μM, but the highest dose (500 μM) of BAC and BMAC increased the heart rates. In addition, AC, MAC, and HAC exhibited serious organic and functional toxicities, while BAC, BMAC, and BHAC did not. It could be induced that DDAs expressed stronger cardiotoxicities than MDAs, which might be due to that they were known as the Na+ channel activators and K+ channel inhibitors, respectively. The β-acetate at C-8 position, along with the protonated nitrogen on ring A of their chemical structures contributed more for their different cardiotoxicities. This is the first study on cardiotoxicity comparison of DAs, providing references for the rational and safe application of these compounds and some plant species containing them to reduce side effects while retaining therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Three new diterpene alkaloids, (+)-8-epiagelasine T (1), (+)-10-epiagelasine B (2), and (+)-12-hydroxyagelasidine C (3), along with three known compounds, (+)-ent-agelasine F (4), (+)-agelasine B (5), and (+)-agelasidine C (6), were isolated from the sponge Agelas citrina, collected on the coasts of the Yucatán Peninsula (Mexico). Their chemical structures were elucidated by 1D and 2D NMR spectroscopy, HRESIMS techniques, and a comparison with literature data. Although the synthesis of (+)-ent-agelasine F (4) has been previously reported, this is the first time that it was isolated as a natural product. The evaluation of the antimicrobial activity against the Gram-positive pathogens Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis showed that all of them were active, with (+)-10-epiagelasine B (2) being the most active compound with an MIC in the range of 1–8 µg/mL. On the other hand, the Gram-negative pathogenes Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were also evaluated, and only (+)-agelasine B (5) showed a moderate antibacterial activity with a MIC value of 16 μg/mL.

The genus Delphinium is a rich source of diterpene alkaloids. Chemical investigation on an alkaloid rich extract of the whole parts of Delphinium turkmenum resulted in the isolation of three C 19 -diterpene alkaloids ( 1-3 ) and a palmitic acid derivative ( 4 ). The chemical structures were elucidated by analysis of 1D and 2D-NMR and comparison the data with those reported in the literature. Notably, all isolated compounds were reported for the first time from D. turkmenum.

The data on antiarrhythmic drugs based on diterpene alkaloid lappaconitine are summarized. N-Deacetyllappaconitine is the main metabolite of allapinin and a potential antiarrhythmics for intravenous use. The basicity of two nitrogen atoms of this compound and the possibility of obtaining mono- and di-salts with the example of hydrochlorides and hydrobromides having good solubility in water have been studied. It was shown using NMR spectroscopy and potentiometric titration that in the methanolic solutions the atom N(20) is protonated at the first step (pKb1 = 6.77, 25 °C) in the pH range of 6—7. The nitrogen of the primary aromatic amino group is protonated in the pH range of 2—3 (pKb2 = 2.18, 25 °C). [ABSTRACT FROM AUTHOR]

Abstract: Aconitum Heterophyllum (A. Heterophyllum) is an indigenous medicinal plant of India and belongs to the family Ranunculaceae. A. Heterophyllum is known to possess a number of therapeutic effects. For very ancient times, this plant has been used in some formulations in the traditional healing system of India, i.e., Ayurveda. It is reported to have use in treating patients with urinary infections, diarrhea, and inflammation. It also has been used as an expectorant and for the promotion of hepatoprotective activity. The chemical studies of the plant have revealed that various parts of the plant contain alkaloids, carbohydrates, proteins and amino acids, saponins, glycosides, quinones, flavonoids, terpenoids, etc. In the present study, a comprehensive phytochemistry and pharmacognosy, as well as the medicinal properties, of A. Heterophyllum are discussed. Abstract: Scientific information on the plant was collected from various sources,

The taproot of Aconitum carmichaelii Debeaux (AC), a poisonous Traditional Chinese Medicine, has been widely used to treat joint pain, rheumatism and dysmenorrhea. Fermentation is a traditional drug processing method that reduces toxicity or increases efficacy. However, the chemical composition of AC, especially fermented AC, has not been fully elucidated. Therefore, it is necessary to establish a method to characterize the chemical composition of raw and fermented AC. In this study, a structural feature-based comprehensive strategy was employed to identify the chemical components of raw and fermented AC. A highly selective method consisting of mass defect filtering (MDF), ring double bond (RDB), nitrogen rule, and feature MS fragments filtering was established using UPLC-Q-Orbitrap-MS. By the established method, 230 diterpene alkaloids were characterized in raw AC, including 108 amine, 68 monoester, and 54 diester diterpene alkaloids. 145 of them were potential new compounds. Totals of 466 diterpene alkaloids were identified in fermented AC, including 231 amine, 162 monoester, and 73 diester diterpene alkaloids. 397 of them were potential new compounds. Ester hydrolysis, hydroxylation, and demethylation were the major transformation pathways during fermentation. An integrated approach with highly selective based on the structural feature of analytes was established and applied to identify the chemicals in AC. The strategy showed great performance in improving the accuracy and coverage of the identification by using LC-MS., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Amides were prepared from N-deacetyllappaconitine and unsaturated oleic, linoleic, α-linolenic, and γ-linolenic fatty acids. [ABSTRACT FROM AUTHOR]

Amides were prepared from N-deacetyllappaconitine and the amino acids glycine, taurine, and γ-aminobutyric acid. [ABSTRACT FROM AUTHOR]

Repeated administration of songorine to mice restored mnestic processes impaired by scopolamine treatment, which manifested in improvement of CPAR conditioning and normalization of behavioral activity throughtout the observation period. This thearpeutical effect surpassed that of pyracetam used as the reference drug. [ABSTRACT FROM AUTHOR]

Aconitum carmichaelii is an important medicinal herb used widely in China, Japan, India, Korea, and other Asian countries. While extensive research on the characterization of metabolic extracts of A. carmichaelii has shown accumulation of numerous bioactive metabolites including aconitine and aconitine-type diterpene alkaloids, its biosynthetic pathway remains largely unknown. Biosynthesis of these secondary metabolites is tightly controlled and mostly occurs in a tissue-specific manner; therefore, transcriptome analysis across multiple tissues is an attractive method to identify the molecular components involved for further functional characterization. In order to understand the biosynthesis of secondary metabolites, Illumina-based deep transcriptome profiling and analysis was performed for four tissues (flower, bud, leaf, and root) of A. carmichaelii, resulting in 5.5 Gbps clean RNA-seq reads assembled into 128,183 unigenes. Unigenes annotated as possible rate-determining steps of an aconitine-type biosynthetic pathway were highly expressed in the root, in accordance with previous reports describing the root as the accumulation site for these metabolites. We also identified 21 unigenes annotated as cytochrome P450s and highly expressed in roots, which represent candidate unigenes involved in the diversification of secondary metabolites. Comparative transcriptome analysis of A. carmichaelii with A. heterophyllum identified 20,232 orthogroups, representing 30,633 unigenes of A. carmichaelii, gene ontology enrichment analysis of which revealed essential biological process together with a secondary metabolic process to be highly enriched. Unigenes identified in this study are strong candidates for aconitine-type diterpene alkaloid biosynthesis, and will serve as useful resources for further validation studies. [ABSTRACT FROM AUTHOR]

Methyllycaconitine and the new C-diterpene alkaloid flexiosine were isolated from roots of Delphinium flexuosum M. Bieb. The structure of the latter was elucidated using PMR, C NMR, and IR spectroscopy and mass spectrometry. [ABSTRACT FROM AUTHOR]

Heritable fungal endosymbiosis is underinvestigated in plant biology and documented in only three plant families (Convolvulaceae, Fabaceae, and Poaceae). An estimated 40% of morning glory species in the tribe Ipomoeeae (Convolvulaceae) have associations with one of two distinct heritable, endosymbiotic fungi (Periglandula and Chaetothyriales) that produce the bioactive metabolites ergot alkaloids, indole diterpene alkaloids, and swainsonine, which have been of interest for their toxic effects on animals and potential medical applications. Here, we report the occurrence of ergot alkaloids, indole diterpene alkaloids, and swainsonine in the Convolvulaceae; and the fungi that produce them based on synthesis of previous studies and new indole diterpene alkaloid data from 27 additional species in a phylogenetic, geographic, and life-history context. We find that individual morning glory species host no more than one metabolite-producing fungal endosymbiont (with one possible exception), possibly due to costs to the host and overlapping functions of the alkaloids. The symbiotic morning glory lineages occur in distinct phylogenetic clades, and host species have significantly larger seed size than nonsymbiotic species. The distinct and widely distributed endosymbiotic relationships in the morning glory family and their alkaloids provide an accessible study system for understanding heritable plant-fungal symbiosis evolution and their potential functions for host plants., (© 2023 The Authors. New Phytologist © 2023 New Phytologist Foundation. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

The formation of negative ions of some diterpene alkaloid molecules having conjugated π and π bonds in their structure by resonance electron capture has been studied. The mass spectra of these compounds are due to electron capture onto the lowest unoccupied molecular orbital (LUMO), which is π*- or π*- in nature. It has been found that the partial conversion of the test compound molecules into the enol form is possible on transferring into a gas phase; for this purpose, the appearance potentials of the ions (M-H) and (M-OCH) have been compared with the calculated thermodynamic thresholds of their appearance in the keto and enol forms. [ABSTRACT FROM AUTHOR]

Oxidation of the diterpene alkaloids lappaconitine, triacetyllappaconine, and talatisamine by the urea-HO complex (UHP) under various conditions produced the corresponding nitrones. [ABSTRACT FROM AUTHOR]

Aconitum and its products have been used in Asia for centuries to treat various ailments, including arthritis, gout, cancer, and inflammation. In general, their preparations and dispensing have been restricted to qualified folk medicine healers due to their low safety index and reported toxicity. In the past few decades, official guidelines have been introduced in Asian pharmacopeias to control Aconitum herbal products. However, these guidelines were based on primitive analytical techniques for the determination of the whole Aconitum alkaloids and were unable to distinguish between toxic and nontoxic components. Recent advances in analytical techniques, especially high performance liquid chromatography (HPLC) and electrophoresis coupled with highly sensitive detectors, allowed rapid and accurate determination of Aconitum secondary metabolites. Reports focusing on liquid chromatography/mass spectrometry analysis of Aconitum and its herbal products are discussed in the current review. This review can be used by the health regulatory authorities for updating pharmacopeial guidelines of Aconitum and its herbal products. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a brain disease characterized by gradual memory loss and cognitive impairments. Acetylcholinesterase (AChE) inhibitors-such as donepezil, memantine, and tacrine-are FDA-approved medications for AD treatment. Due to the lack of their efficacy and higher side effects, many researchers have been searching for effective and safer alternatives. In this study, experimentally proved phytochemicals against brain diseases were screened based on their binding energies to the target site of AChE, pharmacokinetic properties, and drug-likeness. Although some phytochemicals showed higher binding affinities than the control drug (donepezil), they did not show permeability across the blood-brain barrier (BBB). However, berberine, anthocyanin, and diterpene alkaloid can cross the BBB and showed good binding affinities of -10.3, -10.1, and -10.2 kcal/mol, respectively. MD simulation and PCA of the simulation data of the protein and protein-ligand complexes proved that the complexes are stable in the biological environment. A total of 16 derivatives of berberine and 3 derivatives of anthocyanin also showed higher binding energies compared to the binding affinity (-11.5 kcal/mol) of the donepezil. The derivatives were designed by substituting -F, -CF3, -CN, and -NH2, and provided higher docking scores due to increasing of nonbonding interactions. MM/GBSA calculations show that the binding free energies of the best predicted derivatives of diterpene alkaloid, anthocyanin, and berberine (DA22, AC11, and BB40) are -100.4 ± 8.4, -79.3 ± 8.7, and -78.3 ± 10.7 kcal/mol, respectively, with the protein. Overall, this study was successful in finding new, highly effective, and possibly safer inhibitors of AChE.Communicated by Ramaswamy H. Sarma.

We compared analgesic activities of individual alkaloids extracted from Baikal aconite ( Aconitum baikalensis): napelline, hypaconitine, songorine, mesaconitine, 12-epinapelline N-oxide. The detected analgesic activity was comparable to that of sodium metamizole. The mechanisms of analgesia were different in diterpene alkaloids of different structure. The antinociceptive effect of atisine alkaloids (12-epinapelline N-oxide, songorine) was naloxonedependent and realized via opioid receptor modulation. [ABSTRACT FROM AUTHOR]

Highlights: [•] HPLC–QTOF MS method was developed for comprehensive analysis of Shenfu injection. [•] A total of 44 compounds were characterized by HPLC–QTOF MS. [•] Twenty-four major alkaloids and ginsenosides were quantified by HPLC–MS. [•] Similarity analyses for Shenfu injection demonstrated high quality consistency. [ABSTRACT FROM AUTHOR]

We compared anti-inflammatory activity of individual diterpene alkaloids isolated from Aconitum baikalense (napelline, songorine, hypaconitine, mesaconitine, 12-epinapelline N-oxide) under conditions of acute inflammation of different genesis. The tested substances showed high antiexudative activity comparable with that of sodium diclofenac. Unlike nonsteroidal anti-inflammatory drugs, diterpene alkaloids exerted no ulcerogenic effect. [ABSTRACT FROM AUTHOR]

Abstract: Diterpene alkaloids neoline (1), napelline (2), isotalatizidine (3), karakoline (4), senbusine A (5), senbusine C (6), aconitine (7) and taurenine (8) were identified from Aconitum napellus L. subsp. firmum, four (2–4, 6) of which are reported for the first time from this plant. The structures were determined by means of LC–MS, 1D and 2D NMR spectroscopy, including 1H–1H COSY, NOESY, HSQC and HMBC experiments. Electrophysiological effects of the isolated compounds, together with nine diterpene alkaloids previously obtained from Aconitum toxicum and Consolida orientalis were investigated on stable transfected HEK–hERG (Kv11.1) and HEK–GIRK1/4 (Kir3.1 and Kir3.4) cell lines using automated patch clamp equipment. Significant blocking activity on GIRK channel was exerted by aconitine (7) (45% at 10μM), but no blocking activities of the other investigated compounds were detected. The tested compounds were inactive on hERG channel in the tested concentration. The comparison of the previously reported metabolites of A. napellus subsp. firmum and compounds identified in our experiment reveals substantial variability of the alkaloid profile of this taxon. [Copyright &y& Elsevier]

Allapinin (lappaconitine hydrobromide) is a drug used for the treatment of cardiac rhythm disturbances; its properties are characteristic of class IC antiarrhythmics. The mechanism of its electrophysiological action involves the blockade of Na channels with a subsequent decrease of depolarization rate leading to a slowing of impulse propagation and a decrease of excitability in the conductive system of the heart. Factors underlying the side effects of Allapinin (tachycardia, arterial hypertension, impaired coordination, etc.) are currently unknown, and therefore a study of the molecular mechanisms of its action seems relevant. The target genes of the drug were identified in rats with induced aconitine arrhythmia using the commercially available Rat Neuroscience Ion Channels & Transporters RT Profiler™ PCR Array kit (SA Biosciences). A comparison of expression levels of 84 genes in rats treated with Allapinin, after the induction of arrhythmia by aconitine (experiment) and in physiological saline-treated arrhythmic rats (control), revealed 18 mRNAs which were up- or downregulated twofold or more in the experiment relative to the control. Allapinin was shown to stimulate the expression of genes coding for various types of K channels ( kcna6, kcnj1, kcnj4, kcnq2, and kcnq4), Ca channel ( cacna1g), and vesicular acetylcholine transporter ( slc18a3). A decrease in mRNA levels was detected for genes coding for K channels ( kcne1, kcns1), a Na channel ( scn8a), and membrane transporter genes ( atp4a, slc6a9). Our data shows that Allapinin administered to animals with aconitine arrhythmia modulates the expression of genes accounting for ion current conductances involved in the formation of various phases of action potential ( I, I, I, I, I). The effect of the drug on the levels of mRNAs coding for acetylcholine and glycine transporters suggests the involvement of these neuromediators in the mechanisms underlying the antiarrhythmic effect of Allapinin. [ABSTRACT FROM AUTHOR]

The effects of complex extract from Aconitum baikalense on reparative regeneration of a plane dorsal skin wound were studied. Treatment with Aconitum baikalense tincture stimulated reparation and skin regeneration. The effects of the Aconitum baikalense alkaloids on functional activity of fibroblast precursors were studied in vitro by cultural methods. Mesaconitine, hypaconitine, songorine, napelline, and 12-epinapelline N-oxide significantly stimulated the growth of colonies from fibroblast precursors. This indicated direct stimulation of fibroblasts by aconite alkaloids, which could be a mechanism of reparative activity of the complex extract. [ABSTRACT FROM AUTHOR]

Course treatment with diterpene alkaloids of Aconitum baicalense in mice reduced the time of immobilization in the tail suspension test and produced an antiexudative effect in mouse model of serotonin-induced edema. In the open fi eld test, application of alkaloids did not change the total motor activity, orientation and exploratory behavior, and emotional reactions of animals. Experimental data suggest that diterpene alkaloids of Aconitum baicalensis exhibit antidepressant properties, possibly due to modulation of sensitivity to serotonin. [ABSTRACT FROM AUTHOR]

Abstract: By optimizing the extraction and analytical conditions, a reliable and precise HPLC method coupled with photodiode array detection (HPLC–DAD) has been developed for the identification and quantification of three major aconitine-type alkaloids (aconitine, mesaconitine, hypaconitine) in the roots of Aconitum carmichaelii Debeaux. The qualitative analysis of the plant material was carried out by LC-APCI-MS n . By means of this method, 26 lipo-alkaloids were also identified from the roots of A. carmichaelii. The effect of processing on aconitine-type alkaloids, lipo-alkaloids and pure aconitine was studied. As part of our investigation, two lipo-alkaloids, 14-benzoylaconine-8-palmitate and 14-benzoylaconine-8-linoleate were produced semisynthetically. The COX-1, COX-2 and LTB4 formation inhibitory activity of aconite root extracts and different types of diterpene alkaloids and the toxicity of lipo-alkaloids were also investigated. [Copyright &y& Elsevier]

Lappaconitine and N-deacetyllappaconitine derivatives containing bromine and iodine atoms in the aromatic moiety were synthesized. The Heck cross-coupling of these halides with ethyl acrylate or 2-methyl-5-vinylpyridine afforded new olefinated lappaconitine derivatives. [ABSTRACT FROM AUTHOR]

Extracts of Aconitum septentrionale Koelle roots obtained using chloroform, isopropanol, and ethanol were purified using chloroform and basic γ-Al2O3. Ballast materials were selectively adsorbed by γ-Al2O3, increasing the mass fraction of lappaconitine in the extract. The ethanol extract was purified most. The degree of lappaconitine extraction by chloroform was unaffected by the presence of γ-Al2O3. However, the mass fraction in the extract and lappaconitine extraction from Aconitum septentrionale were increased more than twice. [ABSTRACT FROM AUTHOR]

Abstract: Rapid access to the ABCE ring system of the C-20 diterpene alkaloids was achieved by silver (I) promoted intramolecular Friedel–Crafts arylation of a functional group specific 5-bromo-3-azabicyclo[3.3.1]nonane derivative. [Copyright &y& Elsevier]

Abstract: Aerial parts of Aconitum variegatum L. from the Pyrenees furnished four norditerpene alkaloids, 16β-hydroxycardiopetaline, 8-ethoxysachaconitine, 14-acetylgenicunine B, N-deethyl-N-19-didehydrosachaconitine, five diterpene alkaloids 15-veratroyldictizine, 15-veratroyl-17-acetyldictizine, 15-veratroyl-17-acetyl-19-oxodictizine, N-ethyl-1α-hydroxy-17-veratroyldictizine, variegatine and the known alkaloids sachaconitine, 14-O-acetylsachaconitine, karakoline, talatizamine, 10-hydroxytalatizamine, 14-acetyltalatizamine, 14-acetyl-10-hydroxytalatizamine, N-methylarmepavine, pengshenin B, delsoline, dihydrodelsoline, delcosine and genicunin B. Structures of the alkaloids were established by MS, 1D- and 2D-NMR techniques. [Copyright &y& Elsevier]