Addictive evaluation of cholic acid-verticinone ester, a potential cough therapeutic agent with agonist action of opioid receptor.
OBJECTIVE
The purpose of this work was to search for potential drugs with potent antitussive and expectorant activities as well as a low toxicity, but without addictive properties. Cholic acid-verticinone ester (CA-Ver) was synthesized based on the clearly elucidated antitussive and expectorant activities of verticinone in bulbs of Fritillaria and different bile acids in Snake Bile. In our previous study, CA-Ver showed a much more potent activity than codeine phosphate. This study was carried out to investigate the central antitussive mechanism and the addictive evaluation of CA-Ver.


METHODS
Testing on a capsaicin-induced cough model of mice pretreated with naloxone, a non-selective opioid receptor antagonist, was performed for the observation of CA-Ver's central antitussive mechanism. We then took naloxone-induced withdrawal tests of mice for the judgment of CA-Ver's addiction. Lastly, we determined the opioid dependence of CA-Ver in the guinea pig ileum.


RESULTS
The test on the capsaicin-induced cough model showed that naloxone could block the antitussive effect of CA-Ver, suggesting the antitussive mechanism of CA-Ver was related to the central opioid receptors. The naloxone-urged withdrawal tests of the mice showed that CA-Ver was not addictive, and the test of the opioid dependence in the guinea pig ileum showed that CA-Ver had no withdrawal response.


CONCLUSIONS
These findings suggested that CA-Ver deserved attention for its potent antitussive effects related to the central opioid receptors, but without addiction, and had a good development perspective.
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China.
Jiu-liang
JL
Zhang
Hui
H
Wang
Chang
C
Chen
Hui-fang
HF
Pi
Han-li
HL
Raun
Peng
P
Zhang
Ji-zhou
JZ
Wu
D000818:Animals; D000996:Antitussive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D002211:Capsaicin; D002595:Cevanes / Q000009:adverse effects / Q000138:chemical synthesis / Q000627:therapeutic use; D002793:Cholic Acids / Q000009:adverse effects / Q000138:chemical synthesis / Q000627:therapeutic use; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009293:Opioid-Related Disorders; D011957:Receptors, Opioid / Q000819:agonists*; D013375:Substance Withdrawal Syndrome
D000996:Antitussive Agents; D002595:Cevanes; D002793:Cholic Acids; D011957:Receptors, Opioid; C542587:cholic acid-verticinone ester; D009270:Naloxone; D002211:Capsaicin