Effects of Aconitum alkaloid kobusine and pseudokobusine derivatives on cutaneous blood flow in mice.
Aconitum alkaloids of the C20-diterpenoid type, kobusine (1) and pseudokobusine (2), and their acetyl, benzoyl, propionyl or cinnamoyl derivatives are examined for their peripheral vaso-activities by laser-flowmetrical measurement of the cutaneous blood flow in the hind foot of mice after intravenous administration. A dose-relationship of maximally increased blood flow after the administration of either of the Aconitum alkaloids existed. Kobusine 15-acetate (4), 11-benzoate (6) and 15-benzoate (7) were significantly effective at a low dose of 1 mg/kg, whereas the other kobusine derivatives were all inactive. Alkaloid 2, alone, and the 11-acetate (14), 15-acetate (15), 15-propionate (22) and 15-cinnamoate (25) were all active at 1 mg/kg and the effect of 14 at 5 mg/kg was remarkable. The activity of 2 was abolished by esterification of the hydroxyl group at C-6. Alkaloid 15 at 5 mg/kg showed a pattern of time course of blood flow in which the increase was rapidly replaced with a decrease below the basal flow, probably suggesting the effect of excessive doses. Conclusively, it is considered that the hydroxyl groups of alkaloids, especially a free OH group of 2 at C-6, are important for action on the peripheral vasculature leading to dilatation, and these results indicated that esterification of the hydroxyl group at C-15 with either acetate or benzoate may contribute to enhancement of the activity of the parent alkaloids.
Wada
K
K
Hokkaido College of Pharmacy, Otaru, Japan.
Ishizuki
S
S
Mori
T
T
Fujihira
E
E
Kawahara
N
N
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply*; D013057:Spectrum Analysis; D014665:Vasodilator Agents / Q000494:pharmacology*
D000470:Alkaloids; D001952:Bridged-Ring Compounds; D004224:Diterpenes; D010616:Phenanthrenes; D011083:Polycyclic Compounds; D014665:Vasodilator Agents; C111428:kobusine; C111430:pseudokobusine