Abstract
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 [3H]diprenorphine and stimulating guanosine 5′-O-(3-[35S]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 ED50 value of 0.25 mg/kg s.c. and more potent antimorphine effect with an ED50 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.
Footnotes
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This work was supported in part by National Basic Research Program and the 863-High Technology Research and Development Program Plan Grant of China.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.099937.
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ABBREVIATIONS: LAAM, l-α-acetylmethadol; thienorphine, N-cyclopropylmethyl-7α-[(R)-1-hydroxy-1-methyl-3-(thien-2-yl)-propyl]-6,14-endo-ethanotetrahydronororipavine; i.g., intragastric; CHO, Chinese hamster ovary; CHO-μ, Chinese hamster ovary cells stably expressing rat μ-opioid receptor; CHO-δ, Chinese hamster ovary cells stably expressing rat δ-opioid receptor; CHO-κ, Chinese hamster ovary cells stably expressing rat κ-opioid receptor; % MPE, maximal possible effect; [35S]GTPγS, guanosine 5′-O-(3-[35S]thio)triphosphate.
- Received December 14, 2005.
- Accepted March 24, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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