A QSAR analysis of toxicity of Aconitum alkaloids

Abstract

Biological activity of Aconitum alkaloids may be related to their toxicity rather than to a specific pharmacological action. A Quantitative structure-activity relationships (QSAR) analysis was performed on the following two groups of alkaloids: compounds with an aroyl/aroyloxy group at R(14) position (yunaconitine, bulleyaconitine, aconitine, beiwutine, nagarine, 3-acetyl aconitine, and penduline), and compounds with the aroyloxy group at R(4) position (N-deacetyllappaconitine, lappaconitine, ranaconitine, N-deacetylfinaconitine, N-deacetylranaconitine). The LD(50) (micromol/kg) of the 12 alkaloids were obtained from the literature. LD(50) was significantly lower in group 1 than in group 2. The steric and core-core repulsion energies were significantly higher in group 1. The total energy and heat of formation and electronic energies were significantly lower in group 1. The reactivity index of N, C1', C4' and C6' were similar between groups. The reactivity index of C2' was significantly higher and the reactivity index of C3' and C5' were significantly lower in group 1. Log P and pKa were similar between groups. Molecular weight was significantly higher in group 1. A significant linear relationship was observed between log LD(50) and either analgesic log ED(50) or local anesthetic log ED(50). The LD(50)/analgesic ED(50) obtained from average values was 5.9 for group 1 and 5.0 for group 2. However, the LD(50)/local anesthetic ED(50) was 40.4 and 318, respectively. The study supports that the analgesic effects of these alkaloids are secondary to their toxic effects whereas alkaloids from group 2 are susceptible to be further studied as local anesthetic agents.

Simultaneous quantification of nine aconitum alkaloids in Aconiti Lateralis Radix Praeparata and related products using UHPLC–QQQ–MS/MS

“…The detection of the three alkaloids at such a high rate implies that there may be unknown risks for patients who consume Fuzi or Fuzi-containing products. One of the major alkaloids in A. vilmorinianum , A. hemsleyanum and A. nagarum is YAC 19 . The roots of the above species are occasionally misrepresented as Radix Aconiti Kusnezoffii and used as “Caowu” (in Chinese) in Chinese herbal medicine.…”

Determination of aconitine, hypaconitine and mesaconitine in urine using hollow fiber liquid-phase microextraction combined with high-performance liquid chromatography

“…The results showed that the extraction efficiency of these analytes increased as the pH became lower, and none of the three analytes could be extracted when pH was higher than 3.0. This is in accordance with what the literature pointed out that the pH of acceptor phase should be at least 2-3 units different from the pK a values of the analytes [24], and the pK a of these aconitines is nearly 6 [27]. Thus, 10.0 mmol/L HCl (pH 3.0) was adopted as the acceptor phase in the following studies.…”

Activities of Naturally Occurring Alkaloids Bulleyaconitine A

“…[4,5,22] It is possible that the biological activity of bulleyaconitine A may be caused by its toxicity rather than a specific pharmacological action. [23] However, King's group found that the anti-hypersensitivity of bulleyaconitine A can be separated from its neurotoxicity by the mechanism of action, [24] and the relatively wide therapeutic window of bulleyaconitine A suggests that its antinociception could be separated from its toxicity. [13] It means that bulleyaconitine A performs its ability by a specific pharmacological action in some way rather than its toxicity.…”