TH-030418: a potent long-acting opioid analgesic with low dependence liability

Abstract

Numerous efforts have been made on the chemical modification of opioid compounds, with the ultimate goal of developing new opioid analgesics that is highly potent and low/non-addictive. In a search for such compounds, TH-030418 [7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydrooripavine] was synthesized. Here, we evaluated the pharmacological activities of TH-030418, in comparison with morphine, the prototype opioid analgesic. In radioligand binding assays, TH-030418 bound potently and nonselectively to μ-, δ-, κ-, and ORL1 (opioid receptor-like 1) receptors stably expressed in CHO (Chinese hamster ovary) cells with K (i) values of 0.56, 0.73, 0.60, and 1.55 nM, respectively. When administered subcutaneously, TH-030418 was much more potent than morphine in analgesia, with the ED(50) values of 1.37 μg/kg and 1.70 μg/kg in hot plate and acetic acid writhing tests, respectively. The opioid antagonist naloxone blocked the antinociceptive effect of TH-030418, indicating that the action of TH-030418 was mediated by opioid receptors. The antinociceptive effect of s.c. TH-030418 in hot plate test lasted for more than 12 h, which is much longer than those of morphine (2.5 h) and dihydroetorphine (1.5 h). In addition, naloxone did not precipitate withdrawal syndrome in the mice treated with TH-030418 previously. Most importantly, TH-030418 did not induce conditioned place preference in mice after chronic treatment. These results indicate that TH-030418 is a potent long-acting opioid analgesic with low dependence liability and may be of some value in the development of new analgesics.

C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors

“…This activity is blocked by the opioid antagonist naloxone, indicating high efficacy at MOPr and/or KOPr. 33 Even more closely related to the current series are analogues of 1a having alternative bulky groups at C20. 31 In that series, moderate affinity and efficacy for NOPr was always associated with partial agonism at MOPr and/or KOPr.…”

“… 29 , 30 However, in recent years, it has become apparent that some other members of the orvinol family also interact with NOPr, particularly those with a bulky group attached to C20 (the t -butyl group of buprenorphine fulfils this role). 31 − 33 While it has been possible to introduce good affinity for NOPr, it has proven to be difficult to couple this with moderate efficacy for this receptor without also introducing efficacy for classical opioid receptors, in particular KOPr. The orvinol TH-030418 ( 18 ; Chart 1 ) is reported as having affinity for NOPr virtually equivalent to its affinity for MOPr, KOPr, and DOPr; however, it also displays very potent and efficacious antinociceptive activity in vivo.…”

BU08073 a buprenorphine analogue with partial agonist activity at μ‐receptors in vitro but long‐lasting opioid antagonist activity in vivo in mice

“…The high affinity of the new ligands at NOP receptors relative to buprenorphine is in agreement with the finding of Yu et al . that TH‐030418 (a thienylethyl orvinol analogue) had as high affinity at NOP receptors as at the other opioid receptors (Yu et al ., ). No indication of the efficacy of this compound at NOP receptors was given.…”

Methyl-orvinol—Dual activity opioid receptor ligand inhibits gastrointestinal transit and alleviates abdominal pain in the mouse models mimicking diarrhea-predominant irritable bowel syndrome

“…As methyl-orvinol is a dual activity ligand with an antagonism at KOR, the inhibition was not complete and did not achieve control level. For instance, TH-030148, an orvinol with non-selective ORs agonist and NOP receptor activity, displayed strong antinociceptive action in writhing and hot plate tests, its effect was reversed by naloxone [26]. Two buprenorphine analogs, i- butyl and i- pentyl , which are mixed ORs agonists with partial activity at MOR and high efficacy at KOR in the [ 35 S]GTPγS assay, were effective in para-phenylquinone abdominal stretch assay in mice (ED 50 0.02 mg/kg sc ).…”