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, like buprenorphine, thienorphine bound potently and nonselectively to mu-, delta-, and kappa-opioid receptors stably expressed in CHO (Chinese hamster ovary) cells and behaved as a partial agonist at mu-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 mu-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.