Incarvillateine (1), a new monoterpene alkaloid carrying a characteristic cyclobutane ring, has been found to show significant antinociceptive activity in a formalin-induced pain model in mice. To investigate the correlation between its structure and antinociceptive activity, and especially to study whether a cyclobutane ring is necessary or not for expression of activity, we evaluated the antinociceptive activity of two constructive units of incarvillateine, such as a monoterpene unit (incarvilline, 3) and a phenylpropanoid unit (ferulic acid, 2) in the formalin test, and compared activity of the units with that of incarvillateine. Furthermore, in order to obtain more information about the structure-activity relationships, monoterpene alkaloid derivatives, such as incarvine C (5, a precursor of incarvillateine), incarvine A (4, an ester compound comprised of two monoterpene alkaloids and a monoterpene) and 3,3'-demethoxy-4,4'-dehydroxyincarvillateine (6, a synthetic new compound), were examined. The antinociceptive effect of 3,3'-demethoxy-4,4'-dehydroxyincarvillateine was equal to that of incarvillateine. Meanwhile, the other compounds exhibited no or weak activity. These results suggested that the cyclobutane moiety of incarvillateine plays an important role in expression of antinociceptive action.

Incarvillea sinensis is a wild plant distributed in northern China. The dried whole plant has been traditionally used to treat rheumatism and relieve pain as an ancient Chinese crude drug. To investigate its antinociceptive activity, we evaluated several fractions derived from the methanolic extract of Incarvillea sinensis in the formalin-induced pain model in mice. Incarvillateine, a novel monoterpene alkaloid, has been found to show significant antinociceptive activity. Here we report the antinociceptive activity of incarvillateine and compare its activity with that of morphine. Additionally, we suggest that its action may be related to influence on the central opioid pathways.

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