Thienorphine Is a Potent Long-Acting Partial Opioid Agonist: A Comparative Study with Buprenorphine

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 -, ␦-, and -opioid receptors stably expressed in CHO (Chinese hamster ovary) cells and behaved as a partial agonist at -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 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.Opioid abuse and dependence remain a serious worldwide health problem. The drugs currently in clinical use for treating opioid dependence are either full-opioid agonist, methadone, and LAAM or antagonist naltrexone (Johnson et al., 2003). Although these drugs proved extremely effective in reducing illicit opioid use, they have some drawbacks; the agonist merely substitutes one addiction for another, and the antagonist is unable to retain patients in treatment due to a lack of desired positive subjective effects (Johnson et al., 2003). Buprenorphine, a derivative of thebaine, has unique pharmacological properties; it is a high-affinity, low-intrinsic activity agonist at -opioid receptor and has an antagonist activity at -opioid receptor (Cowan et al., 1977;Dum and Herz, 1981;Negus et al., 1989). Buprenorphine, as a partial agonist, either alone or in combination with naloxone, has been shown to be effective in treating opioid dependence experimentally and clinically (for reviews, see Johnson et al., 2003;Davids and Gastpar, 2004). With its unique pharmacological properties, buprenorphine gains advantages over the agonist or antagonist medication in the treatment of opioid addiction, showing an acceptable effectiveness as well as a good safety profile, particularly with respect to lower respiratory depression and physical dependence relative to a full--opioid receptor agonist (Walsh et al., 1994(Walsh et al., , 1995.Buprenorphine is safe and has low abuse liability, whereas its use in the treatment of opioid dependence has been restricted by its very low oral bioavailability (Heel et al., 1979), which results in a somewhat inconvenient administration of sublingual preparations in clinic (Mendelson et al., 1997;Schuh and Johanson, 1999). In addition, it has been shown that buprenorphine can cause dependence both in physical and psychological studies, probabl...

Thienorphine: Receptor Binding and Behavioral Effects in Rhesus Monkeys

“…Consistent with a previous report (Yu et al, 2006), thienorphine bound to -, -, and ␦-opioid receptors. In the previous study, thienorphine produced 62% of maximal stimulation at -receptors (compared with morphine), functioning as a partial -receptor agonist.…”

“…1) is a newly synthesized oripavine derivative (Liu et al, 2005) that reportedly binds to -, -, and ␦-opioid receptors in vitro and has good oral bioavailability in mice (Yu et al, 2006). Furthermore, in mice, thienorphine has potent antinociceptive effects that are thought to be mediated by -opioid receptor agonism (Yu et al, 2006); however, the pharmacological (receptor) mechanism(s) underlying the antinociceptive effects of thienorphine has not been confirmed in other species. The current study evaluated the antinociceptive and other behavioral effects of thienorphine in rhesus monkeys and also examined its receptor binding in cell membrane homogenates.…”

Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418

“…As expected, the receptor binding assay revealed that 030418, a novel 6,14-bridged oripavine compound, displayed nonselective binding affinities to the µ-, κ-, and δ-opioid receptors and the ORL1 receptor with K i values in the nanomolar range, as did thienorphine. Moreover, our observation that thienorphine highly bound to the µ-, κ-, and δ-opioid receptors is in accord with previous reports [15,16] . Consistent with Li et al [16] , thienorphine exhibited partial agonist activity at the κ-opioid receptor and at the µ-opioid receptor (to a lesser extent) but not at the δ-opioid receptor in vitro.…”

“…experimental data regarding the potency of dihydroetorphine and morphine were consistent with those of Aceto et al [34] . In addition, 030418 had more potent and powerful antinociceptive effects in vivo than its parent compound thienorphine, which has previously been demonstrated to be a partial opioid agonist, with an eD 50 value in the milligram range in the mouse antinociceptive tests [15] . Compared with morphine, 030418 shows a rather long-lasting duration of the antinociceptive effect in the hot-plate test, which is similar to thienorphine.…”

“…Inspired by these reports, N-cyclopropylmethyl-7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydronororipavine (thienorphine, Figure 1) was synthesized in our institute [13] . Previous studies have found that thienorphine has a higher potency, longer duration of action, and better oral bioavailability than buprenorphine [14,15] . Therefore, thienorphine has a pharmacological profile that indicates its use as a potential treatment for opiate abuse.…”