Structure-Antinociceptive Activity Studies of Incarvillateine, a Monoterpene Alkaloid from Incarvillea sinensis

Abstract

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 Lam. - Bignoniaceae - incarvillateine - antinociceptive activity - monoterpene alkaloid - phenylpropanoid - cyclobutane ring - formalin-induced pain model

References

• 1 Chi Y-M, Yan W-M, Chen D-C, Noguchi H, Iitaka Y, Sankawa U. A monoterpene alkaloid from Incarvillea sinensis .  Phytochemistry. 1992;  31 2930-2
• 2 Chi Y-M, Yan W-M, Li J-S. An alkaloid from Incarvillea sinensis .  Phytochemistry. 1990;  29 2376-8
• 3 Chi Y-M, Hashimoto F, Yan W-M, Nohara T. Incarvine A, a monoterpene alkaloid from Incarvillea sinensis .  Phytochemistry. 1995;  40 353-4
• 4 Chi Y-M, Hashimoto F, Yan W-M, Nohara T. Two alkaloids from Incarvillea sinensis .  Phytochemistry. 1995;  39 1485-7
• 5 Chi Y-M, Hashimoto F, Yan W-M, Nohara T, Yamashita M, Marubayashi N. Monoterpene alkaloids from Incarvillea sinensis. VI. Absolute stereochemoistry of incarvilline and structure of a new alkaloid, hydroxyicarvilline.  Chem. Pharm. Bull.. 1997;  45 495-8
• 6 Chi Y-M, Hashimoto F, Yan W-M, Nohara T. Four monoterpene alkaloid derivatives from Incarvillea sinensis .  Phytochemistry. 1997;  46 763-9
• 7 Chi Y-M, Hashimoto F, Nohara T, Nakamura M, Yoshizawa T, Yamashita M et al.. Incarvilleae alkaloids and analgesic, sedative substance. 38th Symposium on the Chemistry of Natural Products. Sendai, Japan; October 14, 1996: Symposium Papers 43-8
• 8 Nakamura M, Chi Y-M, Yan W-M, Nakasugi Y, Yoshizawa T, Irino N et al. Strong antinociceptive effect of incarvillateine, a novel monoterpene alkaloid from Incarvillea sinensis .  J. Nat. Prod.. 1999;  62 1293-4
• 9 Baracchi A, Chimichi S, Sio F D, Donati D, Nesi R, Sarti-Fantoni P et al. Preparation of Chloro-α-truxillic acid via 3-methyl-4-nitro-5-styrylisoxazole photodimers.  Heterocycles. 1986;  24 2863-70
• 10 Dubuisson D, Dennis S G. The formalin test: a quantitative study of the analgesic effect of morphine, meperidine, and brain stem stimulation in rats and cats.  Pain. 1977;  4 161-74
• 11 Hunskaar S, Hole K. The formalin test in mice: Dissociation between inflammatory and non-inflammatory pain.  Pain. 1987;  30 103-14