Orvinol-based opioid receptor antagonist fluorinated at C(20)-pharmacophore

Thevinols and their 3-O-demethylated relatives, orvinols, are derivatives of the Diels-Alder adduct of natural alkaloid thebaine with methyl vinyl ketone. Taken together, thevinols and orvinols constitute an important family of opioid receptor (OR) ligands playing an important role in both the OR mediated antinociception and OR antagonism. Herein, we disclose for the first time the antagonist activity of the N-allyl substituted orvinol derivative fluorinated within the pharmacophore associated with C(20) and its surrounding. This compound was prepared via a novel synthetic sequence from 18,19-dihydrothevinone bearing an allyl substituent at N(17) and three fluorine atoms at C(21). Preliminary trials reported earlier demonstrated that the compound exhibited no analgesic activity. However, in vivo experiments conducted in an acute pain model (tail-flick test in mice) demonstrated that this fluorinated compound, when administered at doses of 5–10 mg/kg (sc) 30 min before morphine, exhibited antagonistic activity at the level of naloxone (1 mg/kg, sc) for a longer duration (at least 120 min) compared to naloxone (60 min). Together with the analgesic activity that has been reported for the C(21)-trifluorinated relatives bearing methyl or cyclopropylmethyl substituent at N(17), this result highlights C(21)-fluorinated thevinols and orvinols as the family of opioid receptor ligands (structurally related to buprenorphine, diprenorphine, etc.) covering the full range of activity profiles from agonists to antagonists, which is promising for tuning of their pharmacological properties via a substitution of hydrogen atoms within the pharmacophore associated with C(20) and its surrounding for fluorine. [Display omitted] •The first C(21)-fluorinated orvinol based opioid receptor antagonist.•Opioid antagonist activity comparable to naloxone.•N-Allyl substituent in the fluorinated orvinol renders opioid antagonist activity.•21,21,21-Trifluoroorvinol scaffold for opioid receptor antagonists.•Opioid receptor antagonist fluorinated at C(20)-pharmacophore.