Structure-analgesic activity relationship studies on the C(18)- and C(19)-diterpenoid alkaloids.
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.
Wang
Jian-Li
JL
Department of Chemistry of Medicinal Natural Products, West China of Pharmacy, Sichuan University, P.R. China.
Shen
Xiang-Li
XL
Chen
Qiao-Hong
QH
Qi
Gong
G
Wang
Wei
W
Wang
Feng-Peng
FP
D019342:Acetic Acid / Q000009:adverse effects; D031841:Aconitum / Q000737:chemistry; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D008968:Molecular Conformation; D010146:Pain / Q000139:chemically induced; D010147:Pain Measurement / Q000187:drug effects*; D018517:Plant Roots / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000700:Analgesics; D004224:Diterpenes; D019342:Acetic Acid