A QSAR analysis to explain the analgesic properties of Aconitum alkaloids

Abstract

Aconitum roots are traditionally prescribed for the management of different types of painful affections in Asiatic countries. A quantitative structure-activity relationship (QSAR) analysis was performed to study the effect of chemical substitutes in the analgesic potency of alkaloids available in Chinese Aconitum roots. Using the CAChe program package for biomolecules, molecular modelling was performed in 12 alkaloids previously tested in a model of acetic acid-induced writhing in rats. The ED50 (micromol/kg) was used as the activity parameter. Structural parameters were compared between alkaloids with an aroyl/aroyloxy group at R14 and alkaloids with the aroyloxy group at R4. Single linear regression analyses were performed in order to find the parameters explaining activity. Alkaloids with an aroyl/aroyloxy group at R14 exhibited the highest potency (significantly less ED50). The stability parameters were different between groups, e.g. total energy was -8.0 +/- 0.4 in the potent analgesic alkaloids and -6.7 +/- 0.3 in the weak analgesic alkaloids (P = 0.001). The reactivity index of C2', C3' and C5' of the aromatic ring was also different between groups, e.g. the reactivity index of C5' was 40.8 +/- 0.6 in potent analgesic alkaloids and 48.1 +/- 0.6 in weaker analgesic alkaloids (P < 0.001). Several structural parameters explained analgesic activity of alkaloids, being the reactivity index of C5' on the aromatic group the most important factor (r = 0.89; P < 0.001).

A QSAR Toxicity Study of a Series of Alkaloids with the Lycoctonine Skeleton

“…In the recently reported QSAR analysis of 12 Aconitum alkaloids [7], the authors have identified a number of structural characteristics, chemical manipulation of which might result in both an increase of analgesic potency and a limitation of toxicity. Mono-parameter equations consisting of reactivity index, heat of formation, total, electronic and steric energies, molecular weight and core-core repulsion were selected as statistically significant ones.…”

“…Likewise, toxicity of the alkaloids has been investigated by modifying certain functional groups. Further, a careful literature search has revealed that investigation of diterpene alkaloids by means of QSAR approach has received very little attention and only recently has an attempt been made to perform a QSAR analysis of the analgesic properties for twelve Aconitum alkaloids [7].…”

Aconitum and Delphinium sp. alkaloids as antagonist modulators of voltage-gated Na+ channels

“…Hence only recently a QSAR analysis of the analgesic and anesthetic properties for 12 Aconitum alkaloids (Bello-Ramirez et al, 2003 and 19 nAChR antagonists (Turabekova and Rasulev, 2005) have been reported. The toxicity/activity data available for these alkaloids and the intriguing sodium channels modulation exhibited (openers and blockers in one homologous series) makes them very interesting targets for molecular modelling studies.…”

Preparative separation of C19-diterpenoid alkaloids from Aconitum carmichaelii Debx by pH&#8209;zone-refining counter-current chromatography

“…3 The C 19 -diterpenoid alkaloids are the major bioactive compounds in the tubers of Aconitum carmichaelii and have been widely used due to their predominant analgesic, antipyretic, anti-rheumatoid arthritis, and anti-inflammation effects. 4,5 To further study the biological activities of these alkaloids and to control the quality of this traditional Chinese medicine and its extract, a large quantity of pure compounds are urgently needed. Therefore, the development of an efficient method for the separation and purification of C 19 -diterpenoid alkaloids from Aconitum carmichaelii is required.…”