Separation of tubulin-binding and anti-inflammatory activity in colchicine analogs and congeners.
The effects of colchicine and its analogs on the carrageenin-induced footpad edema in rats were investigated. The anti-inflammatory effects of colchicine analogs were measured at 3 and 5 hr after the carrageenin injection. Colchicine, 1-demethylcolchicine and 3-demethylcolchicine markedly inhibited the carrageenin edema whereas 2-demethylcolchicine was much less active. Thiocolchicinoids, having a thiomethyl group at C-10 instead of a methoxy group, were considerably less potent. These results suggest that the presence of methoxy groups at C-2 and C-10 in colchicine is necessary to maintain anti-inflammatory activity. Inactivity of deacetylcolchicine indicates that substitution of the amino group at C-7 with electron withdrawing groups is also important. Significant inhibition of carrageenin edema and strong binding to tubulin in vitro were manifested by colchicine, 3-demethylcolchicine, N-butyryldeacetylcolchicine and colchifoline. On the other hand, N-carbethoxydeacetylcolchicine which did bind well to tubulin, did not show much effect on the carrageenin edema. These results suggest that the anti-inflammatory action of colchicinoids may not be regulated through the microtubule system.
D000818:Animals; D000893:Anti-Inflammatory Agents; D002351:Carrageenan; D003078:Colchicine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D014404:Tubulin; D002351:Carrageenan; D003078:Colchicine