C(21)-fluorinated thevinol scaffold for opioid ligands. 21,21,21-Trifluoro-6-O-nororvinols: Design, synthesis and analgesic activity

Abstract

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 OR activity of orvinols fluorinated within the pharmocophore associated with C(20) and its surrounding along with a dependence of the activity profile on the substituent at N(17). Starting from thevinone and 18,19-dihydrothevinone, a family of C(21)-fluorinated orvinols bearing methyl, cyclopropylmethyl (CPM), and allyl substituent at N(17) was synthesized. The fluorinated compounds were evaluated for OR activity. The orvinols bearing three fluorine atoms at C(21) were found to retain the properties of OR ligands and their activity profile depends on the substituent at N(17). Pilot in vivo experiments in a model of acute pain (tail-flick test in mice) revealed that 6-O-desmethyl-21,21,21-trifluoro-20-methylorvinol at doses 1.0-10.0 mg/kg (s.c.) exhibits analgesic activity at the level of morphine for a duration of 30-180 min. Its N(17)-CPM counterpart demonstrated the partial opioid agonist properties. The N(17)-allyl substituted derivative showed no analgesic activity. In vivo evaluation of an analgesic activity indicates that 21,21,21-trifluoro-20-methylorvinols represent a novel family of OR ligands related to buprenorphine, diprenorphine, etc. These compounds are promising for the structure-activity relationship studies among the thevinol/orvinol series as well as for a search for new OR ligands with potentially valuable pharmacological profiles.

Keywords: Analgesic activity; Fluorinated opioid ligands; Orvinols; Pharmacophore; Thevinols.