1. Structure-analgesic activity relationship studies on the C(18)- and C(19)-diterpenoid alkaloids.
- Author
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Wang JL, Shen XL, Chen QH, Qi G, Wang W, and Wang FP
- Subjects
- Acetic Acid adverse effects, Aconitum chemistry, Alkaloids chemistry, Alkaloids toxicity, Analgesics chemistry, Analgesics toxicity, Animals, Diterpenes chemistry, Diterpenes toxicity, Drug Evaluation, Preclinical, Female, Mice, Mice, Inbred Strains, Models, Animal, Molecular Conformation, Pain chemically induced, Plant Roots chemistry, Stereoisomerism, Structure-Activity Relationship, Alkaloids pharmacology, Analgesics pharmacology, Diterpenes pharmacology, Pain Measurement drug effects
- Abstract
For evaluation of C(18)- and C(19)-diterpenoid alkaloids as analgesics, three C(19)-diterpenoid alkaloids were isolated from the roots of Aconitum hemsleyanum var. circinatum and A. transsecutum; and twenty-five semisynthetic C(18)- or C(19)-diterpenoid alkaloids were prepared from lappaconitine, crassicauline A or yunaconitine. In a mice acetic acid-induced abdominal constriction assay, four crassicauline A analogs and three yunaconitine analogs exhibited good analgesic activities with 77.8-94.1% inhibition range in 0.1-10 mg/kg subcutaneous (s.c.) dose range at the point of 20 min after drug administration. Among them, 8-O-deacetyl-8-O-ethylcrassicauline A (ED(50)=0.0972 mg/kg) and 8-O-ethylyunaconitine (ED(50)=0.0591 mg/kg) were the most potent analgesics relative to the reference drugs lappaconitine (ED(50)=3.50 mg/kg) and crassicauline A (ED(50)=0.0480 mg/kg). Analgesic activity data of these C(18)- and C(19)-diterpenoid alkaloids indicate that a tertiary amine in ring A, an acetoxyl or an ethoxyl group at C-8, an aromatic ester at C-14, and the saturation state of the ring D are important structural features necessary to the analgesic activity of the C(19)-diterpenoid alkaloids.
- Published
- 2009
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