Structure-antinociceptive activity studies of incarvillateine, a monoterpene alkaloid from Incarvillea sinensis

Incarvillateine (1), a new monoterpene alkaloid carrying a characteristic c yclobutane ring, has been found to shaw significant antinociceptive activit y 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 inc arvillateine, such as a monoterpene unit (incarvilline, 3) and a phenylprop anoid unit (ferulic acid, 2) in the formalin test, and compared activity of the units with that of incarvillateine. Furthermore, in order to obtain mo re information about the structure-activity relationships, monoterpene alka loid derivatives, such as incarvine C (5, a precursor of incarvillateine), incarvine A (4, an ester compound comprised of two monoterpene alkaloids an d a monoterpene) and 3,3'-demethoxy-4,4'-dehydroxyincarvillateine (6, a syn thetic new compound), were examined. The antinociceptive effect of 3,3'-dem ethoxy-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 importan t role in expression of antinociceptive action.