Thienorphine Is a Potent Long-Acting Partial Opioid Agonist: A Comparative Study with Buprenorphine

A strategy in the development of new treatment for opioid addiction is to find partial opioid agonists with properties of long duration of action and high oral bioavailability. In a search for such compounds, thienorphine, a novel analog of buprenorphine, was synthesized. Here, we reported that, lik...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2006-07, Vol.318 (1), p.282-287
Main Authors: Yu, Gang, Yue, Yong-Juan, Cui, Meng-Xun, Gong, Ze-Hui
Format: Article
Language:English
Subjects:
Analgesics, Opioid - administration & dosage
Analgesics, Opioid - chemistry
Animals
Buprenorphine - administration & dosage
Buprenorphine - analogs & derivatives
Buprenorphine - chemistry
Buprenorphine - pharmacology
CHO Cells
Cricetinae
Dose-Response Relationship, Drug
Female
Mice
Pain Measurement - drug effects
Pain Measurement - methods
Protein Binding - drug effects
Protein Binding - physiology
Rats
Receptors, Opioid - agonists
Receptors, Opioid - physiology
Time Factors
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Summary:A strategy in the development of new treatment for opioid addiction is to find partial opioid agonists with properties of long duration of action and high oral bioavailability. In a search for such compounds, thienorphine, a novel analog of buprenorphine, was synthesized. Here, we reported that, like buprenorphine, thienorphine bound potently and nonselectively to μ-, δ-, and κ-opioid receptors stably expressed in CHO (Chinese hamster ovary) cells and behaved as a partial agonist at μ-opioid receptor. However, some differences were observed between the pharmacological profiles of thienorphine and buprenorphine. In vitro, thienorphine was more potent than buprenorphine in inhibiting [ 3 H]diprenorphine and stimulating guanosine 5′- O -(3-[ 35 S]thio)triphosphate binding to rat μ-opioid receptor stably expressed in CHO cells. In vivo, thienorphine exhibited a less potent but more efficacious antinociceptive effect with an ED 50 value of 0.25 mg/kg s.c. and more potent antimorphine effect with an ED 50 value of 0.64 mg/kg intragastric, compared with buprenorphine. Additionally, the bioavailability of thienorphine was greatly higher than that of buprenorphine after oral administration. Moreover, compared with buprenorphine, thienorphine showed a similar long-lasting antinociceptive effect but a much longer antagonism of morphine-induced lethality (more than 15 days). These results indicate that thienorphine is a potent, long-acting partial opioid agonist with high oral bioavailability and may have possible application in treating addiction.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.105.099937