title: 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.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
authors.forename: Angélica M
authors.initials: AM
authors.lastname: Bello-Ramírez
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Nava-Ocampo
mesh_terms: D031841:Aconitum; D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity*; D000700:Analgesics / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D051379:Mice; D008958:Models, Molecular; D008970:Molecular Weight; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000700:Analgesics; D000779:Anesthetics, Local