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.
Yu
Gang
G
Department of Pharmacology, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, Beijing, China.
Yue
Yong-Juan
YJ
Cui
Meng-Xun
MX
Gong
Ze-Hui
ZH
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