Strong Antinociceptive Effect of Incarvillateine, a Novel Monoterpene Alkaloid from Incarvillea sinensis

Nakamura, Motoyuki; Chi, Yu‐Ming; Yan, Wen‐Mei; Nakasugi, Yumiko; Yoshizawa, Toyokichi; Irino, Nobuto; Hashimoto, Fumio; Kinjo, Junei; Nohara, Toshihiro; Sakurada, Shinobu

doi:10.1021/np990041c

Cited by 58 publications

(33 citation statements)

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“…After 1 h reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with CHCl 3 Synthesis of 4,4-Dihydroxy-a a-truxillic Acid Dimethylester (4) To a solution of 4,4Ј-dihydroxy-a-truxillic acid (1.0 g, 3.05 mmol) in methyl ethyl ketone (40 ml) and MeOH (20 ml), trimethylsilyldiazomethane (4 ml) in ether (10 ml) was added dropwise under stirring. After 1 h reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with hexane-AcOEt …”

Section: )mentioning

confidence: 99%

Antinociceptive Activities of .ALPHA.-Truxillic Acid and .BETA.-Truxinic Acid Derivatives

Chi¹,

Nakamura²,

Zhao³

et al. 2006

Biological & Pharmaceutical Bulletin

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In the previous report, we disclosed that a-truxillic acid (1) and its derivative 4,4Ј-dihydroxy-a-truxillic acid (2) showed significant anti-inflammatory activities in the formalin test. Their monomer components (E)-cinnamic acid and (E)-p-coumaric acid exhibited only weak or no activity. 1) This result suggested that the dimeric structure played an important role in the expression of anti-inflammatory activity. In the course of our investigation of antinociceptive substances from natural sources, a novel monoterpene alkaloid, incarvillateine, was characterized from a traditional Chinese crude drug designed as 'Tougucao' (Incarvillea sinensis). 2)Incarvillateine possessed the same dimeric structure as that of a-truxillic acid, and demonstrated more potent antinociceptive activity than morphine in the formalin test.3) The mechanism of antinociception was regarded to be different from that of morphine, and the activity was mainly evoked by activation of m, k-opioid receptors and an adenosine receptor. Structure-activity relationship study of incarvillateine revealed that the monoterpene alkaloid moiety, incarvilline, and the dimeric structure played important roles in the expression of activities against the neurogenic and inflammatory pain responses, respectively. 4) In order to investigate the structure-activity relationship between dimeric structure and anti-inflammatory activity, a-truxillic acid and b-truxinic acid, as well as their derivatives, were prepared (Fig. 1), and their activities were evaluated in the formalin test. MATERIALS AND METHODS AnimalsMale ddy mice were used. The mice (25Ϯ5 g) Our recent study demonstrated that the dimeric structure of a a-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, a a-truxillic acid (1) and its derivatives (2-6), b b-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 a a-truxillic acid (1) and its derivative 4,4-dihydroxy-a a-truxillic acid (2). In addition, a a-truxillic acid (1) and its derivative, a a-truxillic acid bis(p-nitrophenyl)ester (5), showed higher anti-inflammatory activities than b b-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 a a-formation of dimeric structure and the free carboxylic acid were also important for the expression of anti-inflammatory activities. Otherwise, 4,4-dichloro-b b-truxinic acid (8) had higher activity than its parent compound 7; furthermore, 1,3-dibenzoyl-2,4-di(4-chlorophenyl)cy...

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Section: )mentioning

confidence: 99%

Antinociceptive Activities of .ALPHA.-Truxillic Acid and .BETA.-Truxinic Acid Derivatives

Chi¹,

Nakamura²,

Zhao³

et al. 2006

Biological & Pharmaceutical Bulletin

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“…Furthermore, it displayed a significant antinociceptive effect which was partially blocked by pretreatment of naloxone, the narcotic antagonist, in the early phase of the formalin test. 10) In the present study, we used the more selective opioid receptor antagonists nor-BNI, b-FNA and NTI in the formalin test. INCA-induced antinociception in both early and late phases was markedly reduced by s.c. pretreatment with b-FNA, a selective m-opioid receptor antagonist, and nor-BNI, a selective k-opioid receptor antagonist.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggested the possibility that the action of INCA was partially related to its influence on the central opioid pathways. 10) However, details on the pharmacological aspect of the mechanism have not, to our knowledge, been undertaken.…”

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confidence: 99%

Pharmacological Study on the Novel Antinociceptive Agent, a Novel Monoterpene Alkaloid from Incarvillea sinensis

Chi¹,

Nakamura²,

Yoshizawa³

et al. 2005

Biological & Pharmaceutical Bulletin

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Incarvillea sinensis LAM. (Bignoniaceae) is a wild plant distributed in the northern area of China, and dried whole plants have traditionally been used in treating rheumatism and relieving pain as an ancient Chinese crude drug designated "Tougucao". 1) In the course of our investigations of its antinociceptive substances, a number of novel monoterpene alkaloids and macrocyclic spermine alkaloids have been characterized. [2][3][4][5][6][7][8][9] One of the monoterpene alkaloids, incarvillateine (INCA, Fig. 1), demonstrated a significant antinociceptive effect against the mouse pain model induced by formalin. We also reported the antinociceptive effect of INCA and comparison of its action with morphine (MOR). In comparison with antinociceptive effects of different doses of INCA and MOR, the ED 50 values of INCA were about 1.06 (early phase) and 1.33 (late phase) times lower than those of MOR. In addition, the antinociceptive effect of INCA in early phase was partially antagonized by pretreatment with naloxone (a narcotic antagonist, 5 mg/kg, s.c), while the effect of morphine was completely reversed. These results suggested the possibility that the action of INCA was partially related to its influence on the central opioid pathways.10) However, details on the pharmacological aspect of the mechanism have not, to our knowledge, been undertaken.In order to examine the antinociceptive mechanism, some opiate antagonists and adenosine receptor antagonist were administered to mice prior to incarvillateine injection in a formalin test, and the licking time of their pain reaction (paw licking) was measured. MATERIALS AND METHODSChemicals INCA was prepared according to the previous report.2) Nor-binaltorphimine (nor-BNI) and b-funaltrexamine (b-FNA) were purchased from Tocris Cookson (Bristol, U.K.). Naltrindole (NTI) was obtained from Sigma (St. Louis, U.S.A.). Theophylline (THEO) and Tween 80 (polyoxyethylene sorbitan monooleate) were obtained from Nacalai Tesque (Kyoto, Japan). Ringer solution was purchased from Fuso Pharmaceutical (Osaka, Japan).Formalin Test This method represented a modification of that described by Dubuisson and Dennis.11) Male ddy mice (25Ϯ5 g) were used. The tested drugs were prepared as suspensions with 0.5% Tween 80/saline. Since the test has a biphasic pain response with two peaks, from 0 to 10 min (early phase) and from 10 to 30 min (late phase), the time spent licking the injected paw was recorded and the data were expressed as total licking time in the early phase and late phase. Treatments of AntagonistsThe experiments were performed according to a modified method described by Kamei et al. 12) and Santos et al. 13) In measurement of the early phase, b-FNA (40 mg/kg, s.c) and nor-BNI (20 mg/kg, s.c) were administered 24 h before the inducer treatment, while NTI (0.5 mg/kg, s.c) and THEO (5 mg/kg, s.c.) were treated 10 min prior to the inducer injection.In measurement of the late phase, b-FNA and nor-BNI were administered 24 h before the inducer treatment. NTI and THEO were administered at ...

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“…98) This compound has been found to show potent analgesic activity in a formalin-induced pain model in mice and this action was in part blocked by naloxone, indicating a partial interaction with a central opioid mechanism. 99) In subsequent tests on mice, it was observed that the analgesic effect of 91 was significantly blocked by theophylline, an adenosine receptor antagonist, suggesting that the potent antinociceptive action of 91 is mainly mediated via an adenosine receptor mechanism rather than an opiate receptor mechanism. 100) Structure-activity relationship studies suggested that the cyclobutane moiety of 91 plays an important role in expression of antinociceptive action because incarvine C (92) 101) and incarvilline (93), 102) isolated from the same plant, and related compounds lacking the cyclobutane ring exhibited no or weak activity.…”

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Development of New Synthetic Methods and Its Application to Total Synthesis of Nitrogen-Containing Bioactive Natural Products

Kibayashi

2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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A group of naturally occurring substances containing nitrogen is widely distributed in plants as well as in fungi, animal, marine organisms, and insects, and many exhibit significant biological activity. These natural products with a huge variety of chemical structures include antibiotics, antitumor agents, immunostimulants, drugs affecting the cardiovascular and central nervous systems, analgesics etc. The diverse activities and low natural abundance of this group of natural products when coupled with their molecular complexity warrant development of new and efficient synthetic methods and strategy for the total synthesis of these products, in particular alkaloids. The purpose of this review is to describe some of our achievements in the total synthesis of the naturally-occurring bases including the Dendrobatid alkaloids pumiliotoxin B and allopumiliotoxin A, the anitibiotic streptazolin, the tricyclic marine alkaloids isolated from the ascidians such as fasicularin, lepadiformine, and cylindricine C, and the dimeric monoterpene alkaloid incarvillateine as well as the formal total synthesis of the spirocyclic marine alkaloids halichlorine and pinnaic acid, which are isolated from the Japanese marine sponge and the Okinawan bivalve, respectively.

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Strong Antinociceptive Effect of Incarvillateine, a Novel Monoterpene Alkaloid from Incarvillea sinensis

Cited by 58 publications

References 11 publications

Antinociceptive Activities of .ALPHA.-Truxillic Acid and .BETA.-Truxinic Acid Derivatives

Antinociceptive Activities of .ALPHA.-Truxillic Acid and .BETA.-Truxinic Acid Derivatives

Pharmacological Study on the Novel Antinociceptive Agent, a Novel Monoterpene Alkaloid from Incarvillea sinensis

Development of New Synthetic Methods and Its Application to Total Synthesis of Nitrogen-Containing Bioactive Natural Products

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