| Research Abstract |
From Incarvillea sinensis, incarvillateine (INCA), a novel monoterpene alkaloidal derivative, showing significant antinociceptive activity against mouse pain model induced by formalin, was isolated. To examine its mechanism, some opiate antagonists and adenosine receptor antagonists were administered to mice, prior to INCA injection in the formalin test. As a result, it was shown that the antinociceptive effect of INCA was arisen from the strong activation of μ,κ receptors and adenosine receptor. Next, the relationship between the structure and the antinociceptive activity was examined, and it has become clear that the presence of a monoterpene alkaloid and a dimeric structure carrying a cyclobutane is essential for the appearance of the antinociceptive effects. This was supported by the fact that the antinociceptive intensity of synthesized 3,3' demethoxy-4,4'-dehydroxyincarvillateine, was parallel to that of INCA. Additionally, it was also clarified that the diphenylcyclobutane dicarboxilic acid, such as α-truxillic acid and 4,4'-dihydroxy-α-truxillic acid, showed significant antinociceptive activity in the second phase (inflammatory reaction) of formalin-induced pain model in mice. Especially, the antinociceptive effect of 4,4'-dihydroxy-α-truxillic acid on the inflammatory stage was more intensive than that of NSAIDs, such asindomethacin or diclofenac. On the other hand, it was shown to be no side-effects, such as ulcer, which is found in NSAIDs. Furthermore, in order to get the information of their antinociceptive intensities, the their activities of diphenylcyclobutane dicarboxylic acid derivatives in the formalin test were evaluated. Almost compounds showed significant antinociceptive activity in the second phase of formalin-induced pain. A possibility that diphenylcyclobutane dicarboxilic acid derivatives was suggested to become a new type of strong anti-inflaamatory drugs.
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