Antiinflammatory and antiallergic effects of a novel metabolite of Nocardiopsis sp. as a potent protein kinase C inhibitor from microbial origin.
The antiallergic and antiinflammatory effects of the new protein kinase C and calmodulin inhibitor K-252a (8R, 9S, 11S)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11- epoxy-1H,8H,11H-2,7b,11a-triazadibenzo [a,g]cycl oocta [cde] trinden-1-one) were investigated in animal models, and the following results were obtained: 1. Oral administration of K-252a, ketotifen or oxatomide showed a dose-dependent inhibition on 48 h homologous passive cutaneous anaphylaxis in rats and anaphylactic bronchoconstriction in passively sensitized guinea pigs. 2. K-252a (1-100 mg/kg p.o.) exerted a dose-dependent protection against platelet-activating factor (PAF)-induced mortality in mice. This protective effect of K-252a was sustained for 7 h. 3. K-252a (1-100 mg/kg p.o.), as well as dexamethasone (1 mg/kg s.c.), showed remarkable inhibitory effects on rat paw edema induced by carrageenin, zymosan, PAF, and antigen-antibody reaction (passive Arthus reaction) and on the croton oil-induced rat ear edema. On the other hand, indomethacin (10 mg/kg p.o.) significantly inhibited carrageenin-induced edema, but did not inhibit edema induced by other phlogistic agents. Based on these results it is suggested that K-252a, by oral administration, has antiallergic and antiinflammatory effects.
Ohmori
K
K
Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Ishii
H
H
Manabe
H
H
Satoh
H
H
Tamura
T
T
Kase
H
H
D000707:Anaphylaxis / Q000188:drug therapy; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001183:Arthus Reaction / Q000188:drug therapy; D001980:Bronchi / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000188:drug therapy*; D026121:Indole Alkaloids; D008297:Male; D051379:Mice; D009618:Nocardiaceae / Q000378:metabolism*; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D010972:Platelet Activating Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats
D000893:Anti-Inflammatory Agents; D002227:Carbazoles; D026121:Indole Alkaloids; D010972:Platelet Activating Factor; C049985:staurosporine aglycone; D011493:Protein Kinase C