Lappaconine

Toxic and active material basis of Aconitum sinomontanum Nakai based on biological activity guidance and UPLC-Q/TOF-MS technology.[Pubmed:32563055]

J Pharm Biomed Anal. 2020 Sep 5;188:113374.

BACKGROUND: As a folk medicine, Aconitum sinomontanum Nakai (Ranunculaceae, Gaowutou, in Chinese) is used by traditional healers to treat many disorders, including pain and inflammatory diseases, but it exhibits the toxic side effects. This study aimed to obtain toxic extract parts from A. sinomontanum roots and to further evaluate the antinociceptive and anti-inflammatory effects of toxic extract parts on mice. This work also aimed to identify various chemical compositions of the toxic and active extract parts and evaluate the safety profile of this plant. METHODS: Experimental drugs (petroleum ether, chloroform, ethyl acetate, n-butanol, alcohol and water extracts) were obtained through systematic solvent extraction from 95 % ethanol extract from A. sinomontanum roots. An acute toxicity test was conducted to compare the toxicity of different extracts administered at the maximum dose to screen a highly toxic extract. In pharmacodynamic activity analysis, the antinociceptive activity of the A. sinomontanum toxic extract was assessed using an acetic acid-induced abdominal writhing model and a hot plate test. Anti-inflammatory activity was assessed in terms of xylene-induced inflammation. Ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was performed to establish a chromatographic fingerprint and to identify various chemical components of the toxic and active extract. RESULTS: Chloroform, water and n-butanol extracts elicited significant toxic effects and had LD50 of 89.65, 1805.40 and 24409.41 mg/kg, respectively. Antinociceptive and anti-inflammatory activities indicated that the chloroform extract significantly alleviated (p < 0.01) the pain induced by acetic acid with an inhibition rate of 44.7 % (5.9 mg/kg) and 50.4 % (17.7 mg/kg). The chloroform extract also significantly (p < 0.01) increased the latency time during the hot plate test. The latency time at 5.9 and 17.7 mg/kg increased from 15.6 +/- 4.1 s to 47.3 +/- 6.4 s and from 16.3 +/- 3.8 s to 49.8 +/- 7.6 s (p < 0.01), respectively, 2 h after treatment. In the inflammatory test, the chloroform extract significantly reduced (p < 0.01) the xylene-induced mouse ear oedema with an inhibition rate of 45.48 % (5.9 mg/kg) and 51.46 % (17.7 mg/kg), respectively. This result indicated that A. sinomontanum chloroform extract was also the active extract part of A. sinomontanum. Phytochemical analysis revealed the presence of alkaloids in the chloroform extract. A total of 30 compounds were detected, and 23 compounds, including Lappaconine, ranaconidine, 8-O-acetylexcelsine, sinomontanine H, finaconitine, lappacontine, N-dacetyllappaconitine, ranaconitine and isolappaconitine, were identified. CONCLUSIONS: A. sinomontanum chloroform extract possesses antinociceptive and anti-inflammatory activities and exhibits significant toxic effects. Phytochemical analysis indicated that some alkaloids may be the main bioactive ingredient responsible for the toxicity and efficacy of A. sinomontanum. This work contributes to the determination of the safety of the medicinal use of A. sinomontanum roots.

Certain norditerpenoid alkaloids and their cardiovascular action.[Pubmed:9644057]

J Nat Prod. 1998 Jun 26;61(6):743-8.

Thirteen new derivatives of norditerpenoid alkaloids, namely, 8-deacetyl-8-p-aminobenzoyldelphinine (1), 8-deacetyl-8-anthranoyldelphinine (2), 8-deacetyl-8-(4-hydroxy-3-methoxycinnamoyl)delphinine (3), 16-demethoxy-15,16-didehydro-8-p-anisoyl-14-benzoyldelpho nine (4), 6-acetylheteratisine N-oxide (6), 3,8-diacetylfalconerine (7), 8-stearoylfalconerine (8), 8-linolenylfalconerine (9), 13-acetylpyrodelphinine (11), 13-acetyldelphinine N-oxide (13), N-deacetyl-8,9-diacetyllappaconitine (14), 8, 9-(methylenedioxy)Lappaconine (15), and 16-epipyroaconitine N-oxide (17), were prepared, and their structures were established by analysis of spectroscopic data (1D and 2D NMR, HRFABMS). The preliminary in vivo cardiovascular action (hypotensive, bradycardic, and ventricular arrhythmias) of these new compounds was tested in male Sprague-Dawley rats. The results are reported herein.

Mode of antinociceptive and toxic action of alkaloids of Aconitum spec..[Pubmed:9459571]

Naunyn Schmiedebergs Arch Pharmacol. 1998 Jan;357(1):39-48.

Extracts of the plant Aconitum spec. are used in traditional Chinese medicine predominantly as anti-inflammatory and analgesic agents, the latter allegedly equally potent as morphine but without any habit-forming potential. As the only pharmacologically active compounds, the C19 diterpenoid alkaloid aconitine, and some of its derivatives, have been proven to be antinociceptive in different analgesic assays, but the mode of action is unknown. To elucidate the mode of action, ten aconitine-like derivatives were investigated with respect to their affinity for voltage-dependent Na+ channels, the action on synaptosomal Na+ and Ca2+ homoeostasis and their antinociceptive, arrhythmogenic and acute toxic properties. Since aconitine is known to bind to site II of Na+ channels, we determined the affinity of the aconitine-like derivatives in vitro to synaptosomal membranes by the [3H]-batrachotoxinin-binding assay and their properties on intrasynaptosomal concentrations of free Na+ and Ca2+ ([Na+]i and [Ca2+]i), both the latter determined fluorometrically with SBFI and Fura-2 respectively. Furthermore, the alkaloids' arrhythmogenic potential was investigated in guinea-pig isolated atria and the antinociceptive action on formalin-induced hyperalgesia and the acute toxic action estimated in mice. The results show that the alkaloids could be divided into at least three groups. The first is characterized by a high affinity to the site II of Na+ channels (Ki about 1.2 microM), the ability to enhance [Na+]i and [Ca2+]i (EC50 about 3 microM), a strong arrhythmogenic action that starts at about 30 nM, an antinociceptive effect (ED50 about 0.06 mg/kg) and high acute toxicity (LD50 values about 0.15 mg/kg). To this group belong aconitine, 3-acetylaconitine and hypaconitine. The second group, with lappaconitine as the only member, has an affinity to Na+ channels an order of magnitude lower (Ki = 11.5 microM), less acute toxicity (LD50 about 5 mg/kg), and a two orders of magnitude lower antinociceptive action (ED50 about 2.8 mg/kg) and lower cardiotoxicity (bradycardia observed at 3 microM). Additionally, lappaconitine suppresses the increase in [Ca2+]i of aconitine-stimulated synaptosomes and increases the excitation threshold of left atria, indicating an inhibition of Na+ channels. The other derivatives, i.e. delcorine, desoxydelcorine, karakoline, lappaconidine, Lappaconine and lycoctonine, belong to the third group, which has hardly any effects. They have a low affinity to Na+ channels with Ki values in the millimolar range, show no effect on synaptosomal [Na+]i and [Ca2+]i, no arrhythmogenic potential up to 100 microM, no antinociceptive activity and low toxicity with LD50 values greater than 50 mg/kg. For the investigated alkaloids we suggest two different antinociceptive-like modes of action. Aconitine, hypaconitine and 3-acetylaconitine may induce a block of neuronal conduction by a permanent cell depolarisation, whereas lappaconitine might act like local anaesthetics. However, because of the low LD50/ED30 quotients of 2-6, the antinociceptive-like action of the Aconitum alkaloids seems to reflect severe intoxication rather than a specific antinociceptive action. The structure/activity relationship shows that alkaloids that activate or block Na+ channels have a benzoyl ester side chain in the C-14 or C-4 positions respectively, whereas the other compounds lack this group.

The alkaloids of Delphinium cashmirianum.[Pubmed:541686]

J Nat Prod. 1979 Nov-Dec;42(6):615-23.

Dephinium cashmirianum Royle (Ranunculaceae) has yielded the new base cashmiradelphine (12), together with the known alkaloids anthranoyllycoctonine (9), lycaconitine (15), avadharidine (17), lappaconitine (4), and N-deacetyllappaconitine (7). Pyridinium chlorochromate oxidation of lycoctonine furnished the new aldehyde lycoctonal (11). The arrhythmogenic and heart rate effects of several of these diterpenoidal alkaloids have been measured on the isolated guinea atria. Lappaconitine was arrhythmogenic at 10(-4)M concentrations. But in contrast to the reference drug aconitine, lappaconitine did not increase the heart rate. In anesthetized rabbits injected with lappaconitine, N-deacetyllappaconitine, and Lappaconine up to 1 mg/kg, cardiac arrhythmia was quickly observed. Even up to 5 mg/kg, the other substances were non-arrhythmogenic.