Antinociceptive activities of alpha-truxillic acid and beta-truxinic acid derivatives.
Our recent study demonstrated that the dimeric structure of alpha-truxillic acid derivatives played an important role in the expression of their anti-inflammatory activities. In the present report, to investigate the correlation between the structure and anti-inflammatory activity, alpha-truxillic acid (1) and its derivatives (2-6), beta-truxinic acid (7) and its derivatives (8-10) were prepared, and their activities were evaluated in the formalin test. All compounds showed only weak or no activities against the neurogenic pain response, but demonstrated significant activities against the inflammatory pain response induced by formalin. The highest anti-inflammatory activities were observed for alpha-truxillic acid (1) and its derivative 4,4'-dihydroxy-alpha-truxillic acid (2). In addition, alpha-truxillic acid (1) and its derivative, alpha-truxillic acid bis(p-nitrophenyl)ester (5), showed higher anti-inflammatory activities than beta-truxinic acid (7) and the corresponding derivative (10). Furthermore, free carboxylic acids (1, 2) showed higher activities than their dimethyl esters (3, 4) and bis(p-nitrophenyl)ester (5). These results confirmed that the alpha-formation of dimeric structure and the free carboxylic acid were also important for the expression of anti-inflammatory activities. Otherwise, 4,4'-dichloro-beta-truxinic acid (8) had higher activity than its parent compound 7; furthermore, 1,3-dibenzoyl-2,4-di(4-chlorophenyl)cyclobutane (6) also showed strong anti-inflammatory activity. These results suggested that substituents in the phenyl groups were also important for the expression of anti-inflammatory activity. In order to gain information about their activity intensity, the anti-inflammatory activities of 2 and 4,4'-dichlorolated derivatives (6, 8) were compared with that of indomethacin (a nonsteroidal anti-inflammatory drug) in the formalin test. As a result, compounds 2, 6 and 8 showed stronger anti-inflammatory activities than indomethacin. These results suggested that alpha-truxillic acid and beta-truxinic acid derivatives might be developed into a new type of anti-inflammatory drug.
Chi
Yu-Ming
YM
Seiwa Pharmaceutical Ltd., Kitaibaraki, Ibaraki, Japan. chi-59@unimatec.co.jp
Nakamura
Motoyuki
M
Zhao
Xi-Ying
XY
Yoshizawa
Toyokichi
T
Yan
Wen-Mei
WM
Hashimoto
Fumio
F
Kinjo
Junei
J
Nohara
Toshihiro
T
Sakurada
Shinobu
S
D000700:Analgesics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D003503:Cyclobutanes / Q000138:chemical synthesis / Q000494:pharmacology*; D005557:Formaldehyde; D007202:Indicators and Reagents; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003503:Cyclobutanes; D007202:Indicators and Reagents; D005557:Formaldehyde; C003731:truxillic acid; D007213:Indomethacin