Thienorphine

Abstract: Thienorphine is an oripavine with long-lasting antinociceptive effects in mice that are thought to be mediated by μ-opioid receptors. This study examined the receptor binding of thienorphine in cell membrane homogenates and its behavioral effects in rhesus monkeys ( Macaca mulatta ). Affinity and potency were determined using radioligand displacement and stimulation of guanosine 5′- O -(3-[35S]thio)triphosphate binding in C6 (μ, δ) and Chinese hamster ovary (κ) cell membranes. Thienorphine displayed high affinity for κ-, μ-, and δ-opioid receptors with K i values of 0.14, 0.22, and 0.69 nM, respectively. Thienorphine partially stimulated κ-opioid (75%) and μ-opioid (19%) receptors and not δ-opioid receptors. Thienorphine dose-dependently increased tail-withdrawal latency for 50°C water and not 55°C water with effects lasting for more than 7 days. The κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI) (3.2 mg/kg) and a large dose (1.0 mg/kg) of naltrexone prevented thienorphine-induced antinociception. Thienorphine enhanced the antinociceptive effects of morphine and U50,488 [ trans -3, 4-dichloro- N -methyl- N -[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide] with 50°C water; with 55°C water, thienorphine enhanced the effects of morphine and attenuated the effects of U50,488. In other monkeys, thienorphine decreased responding in both components of a multiple schedule of food presentation and stimulus shock termination for up to 8 days; naltrexone and nor-BNI partially prevented these rate-decreasing effects. In morphine-treated monkeys discriminating naltrexone, thienorphine, and U50,488 neither substituted for nor modified the naltrexone discriminative stimulus. Thienorphine and U50,488 produced the same directly observable signs. These results show that thienorphine has long-lasting effects that seem to be mediated by low-efficacy agonism at κ-opioid receptors, both in vitro and in vivo.

Abstract: Thienorphine (TNP) is a novel partial opioid agonist that has completed phase II clinical evaluation as a promising drug candidate for the treatment of opioid dependence. Previous studies have shown that TNP and its glucuronide conjugate (TNP-G) undergo significant bile excretion. The purpose of this study was to investigate the roles of efflux transporters in regulating biliary excretion and plasma exposure of TNP and TNP-G. An ATPase assay suggested that TNP and TNP-G were substrates of P-gp and MRP2, respectively. The in vitro data from rat hepatocytes showed that bile excretion of TNP and TNP-G was regulated by the P-gp and MRP2 modulators. The accumulation of TNP and TNP-G in HepG2 cells significantly increased by the treatment of mdr1a or MRP2 siRNA for P-gp or MRP2 modulation. In intact rats, the bile excretion, and pharmacokinetic profiles of TNP and TNP-G were remarkably changed with tariquidar and probenecid pretreatment, respectively. Tariquidar increased the Cmax and AUC0-t and decreased MRT and T1/2 of TNP, whereas probenecid decreased the plasma exposure of TNP-G and increased its T1/2. Knockdown P-gp and MRP2 function using siRNA significantly increased the plasma exposure of TNP and TNP-G and reduced their mean retention time in mice. These results indicated the important roles of P-gp and MRP2 in hepatobiliary excretion and plasma exposure of TNP and TNP-G. Inhibition of the efflux transporters may affect the pharmacokinetics of TNP and result in a drug-drug interaction between TNP and the concomitant transporter inhibitor or inducer in clinic.