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.
Department of Pharmacology, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, Beijing, China.
Gang
G
Yu
Yong-Juan
YJ
Yue
Meng-Xun
MX
Cui
Ze-Hui
ZH
Gong
D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000737:chemistry*; D000818:Animals; D002047:Buprenorphine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists* / Q000502:physiology; D013997:Time Factors
D000701:Analgesics, Opioid; D011957:Receptors, Opioid; C512397:thienorphine; D002047:Buprenorphine