Addictive evaluation of cholic acid-verticinone ester, a potential cough therapeutic agent with agonist action of opioid receptor

Zhang, Jiu‐liang; Wang, Hui; Chen, Chang; Pi, Hui‐Fang; Raun, Han-li; Zhang, Peng; Wu, Jizhou

doi:10.1038/aps.2009.43

Cited by 21 publications

(19 citation statements)

References 22 publications

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“…G-protein coupled bile acid receptor 1 (GPBAR1, also known as TGR5) agonists have potential for the treatment of diabetes [1][2][3] . Bile acids (BAs), which are essential for dietary lipid absorption and cholesterol excretion, modulate the transcription of genes for enzymes and transport proteins through binding to the farnesoid X receptor (FXR) [4,5] .…”

Section: Introductionmentioning

confidence: 99%

Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy

Wang

Zhang

et al. 2014

Acta Pharmacol Sin

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Aim: TGR5 is a G protein-coupled receptor that is expressed in intestinal L-cells and stimulates glucagon-like peptide 1 (GLP-1) secretion. TGR5 may represent a novel target for the treatment of metabolic disorder. Here, we sought to design and synthesize a series of TGR5 agonists derived from the natural product betulinic acid. Methods: A series of betulinic acid derivatives were designed and synthesized. A cAMP assay was established using a HEK293 cell line expressing human TGR5. Luciferase reporter assay was established using HEK293 cells transfected with plasmids encoding human FXR and luciferase reporter. A human intestinal L-cell line NCI-H716 was used to evaluate the effects of the betulinic acid derivatives on GLP-1 secretion in vitro. Results: Biological data revealed that the 3-α-OH triterpenoids consistently show increased potency for TGR5 compared to their 3-β-OH epimers. 3-OH esterification increased the lipophilicity and TGR5 activity of 3-α betulinic derivatives and enhanced the activity differences between 3-α and 3-β derivatives. The 3-α-acyloxy betulinic acids also exhibited a significant dose-dependent GLP-1 secretion effect. Conclusion: This study demonstrates that highly lipophilic 3-epi-betulinic acid derivatives can be potent and selective TGR5 agonists with improved cellular efficacy, and our research here provides a new strategy for the design and development of potent TGR5 agonists.

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Section: Introductionmentioning

confidence: 99%

Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy

Wang

Zhang

et al. 2014

Acta Pharmacol Sin

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“…21,37) In the present study, mechanical hyperalgesia in the hind paw of the rats was still observed after three week injections of the vehicle, a mixture of saline and Cremophor EL, which is used conventional in the formulation of paclitaxel. The ) and morphine (5 mg/kg, i.p) were administered 3 times a week for 3 weeks (day 8,10,12,15,17,19,22,24,26) from the 8th day after the first paclitaxel injection, when a significant pain threshold decrease was observed versus the vehicle group. Data was expressed as the percentage of the mean pre-paclitaxel control responseϮS.D.…”

Section: Discussionmentioning

confidence: 99%

“…and morphine (5 mg/kg, i.p.) were administered 3 times a week for 3 weeks (day 8,10,12,15,17,19,22,24,26) after one week's administration of paclitaxel.…”

Section: Formalin-induced Behavioural Nociception In Micementioning

confidence: 99%

“…For testing, rats were allowed to acclimate for 10 min. Von Frey filaments (Touch-Test TM Sensory Evaluators; North Coast Medical Supply, Morgan Hill, CA, U.S.A.) ranging 1.0-15.0 g bending force were applied to the medial plantar surface of both hind paws five times, with each application held for 6 s. The Von Frey test was performed before the first drug administration and almost every other day for 4 weeks (briefly on day 0, 2, 4,6,8,10,12,15,17,19,22,24,26). Paw withdrawal threshold was defined as the minimum pressure required to elicit a withdrawal reflex of the paw.…”

Section: Formalin-induced Behavioural Nociception In Micementioning

confidence: 99%

“…13,14) In our previous studies, we also found that verticinone cholic acid ester and verticinone cholic acid salt might activate the opioid system but without inducing addiction, and in which the active center was verticinone. 15,16) As opioid analgesics are still the current standard of care for the treatment of moderate or severe nociceptive pain, 17) this finding prompted us to investigate the analgesic activity of verticinone. In the present study, the acetic acid and formalin induced inflammatory pain model and paclitaxel induced neropathic pain model were adopted to evaluate the analgesic efficacy of verticinone.…”

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confidence: 99%

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Antinociceptive Efficacy of Verticinone in Murine Models of Inflammatory Pain and Paclitaxel Induced Neuropathic Pain

Wang

et al. 2011

Biological & Pharmaceutical Bulletin

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Verticinone, an isosteroidal alkaloid separated from Bulbus Fritillaria (Chinese name "Bei-mu"), was evaluated for its analgesic activities in murine models of inflammatory and neuropathic pain. It was shown that oral administarion of verticinone could significantly inhibit acetic acid-induced writhing response in a dose-dependent way, and the writhing inhibition of 3 mg/kg verticinone was 66.2%, which was approximately higher than that of 200 mg/kg aspirin. In the formalin test, a high dose of (3 mg/kg) verticinone could inhibit the nociceptive response of both phases, but the lower dose (1.5 mg/kg) could only inhibit the second phase response, which suggested that verticinone might exert its analgesic effect through both central and peripheral mechanisms. In addition, in formalin and acetic acid tests, the spontaneous locomotive activities of the mice treated with verticinone were transiently greatly decreased when compared with the vehicle group. In the rat model of paclitaxel induced neuropathic pain, in contrast to the declined analgesic effect of morphine after repeated administration with the same dose, a relatively constant analgesic effect of verticinone was observed. These investigations suggested that verticinone could exert a good antinociceptive effect on inflammatory pain and cancer-related neuropathic pain probably through both peripheral and central mechanisms, and it might be partly involved with some sedation effects. Verticinone is expected to become a potentially novel sedative-analgesic agent without producing tolerance and dependence, but further studies are still urgently needed to elucidate the precise mechanisms and activities of it.

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Progress in growth of large β‐BaB₂O₄ single crystals

Perlov

Livneh

Czechowicz

et al. 2011

Cryst. Res. Technol.

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Growth of large beta-barium borate (BBO) crystals of high optical quality has been challenging, even 25 years past its discovery. The best results in terms of size and quality have been demonstrated by means of TSSG (Top Seeded Solution Growth). Nevertheless, the maximum available size of nonlinear optical elements lags behind laser industry requirements. Due to increased size and availability, BBO finally started attracting attention for its favorable Q-switch properties. Yet, two or sometimes three crystals aligned together are still necessary to achieve the lengths often required for these applications. Material quality, in terms of optical perfection and optical absorption, is still questionable in many instances. Limited boule size still dictates relatively high material cost as well. Thorough analysis of the growth behavior of BBO helped us to develop production processes for large boules utilizing TSSG with pulling. High quality nonlinear optical crystal devices and Q-switches up to 40 mm in the z-direction have been enabled. We believe that the above size and quality are currently industry leading.

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Addictive evaluation of cholic acid-verticinone ester, a potential cough therapeutic agent with agonist action of opioid receptor

Cited by 21 publications

References 22 publications

Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy

Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy

Antinociceptive Efficacy of Verticinone in Murine Models of Inflammatory Pain and Paclitaxel Induced Neuropathic Pain

Progress in growth of large β‐BaB₂O₄ single crystals

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Addictive evaluation of cholic acid-verticinone ester, a potential cough therapeutic agent with agonist action of opioid receptor

Cited by 21 publications

References 22 publications

Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy

Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy

Antinociceptive Efficacy of Verticinone in Murine Models of Inflammatory Pain and Paclitaxel Induced Neuropathic Pain

Progress in growth of large β‐BaB2O4 single crystals

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Progress in growth of large β‐BaB₂O₄ single crystals