title: Methoxyflavones from Stachys glutinosa with binding affinity to opioid receptors: in silico, in vitro, and in vivo studies.
abstract: Fractionation of the bioactive dichloromethane extract from the aerial parts of Stachys glutinosa led to the isolation of four flavones, xanthomicrol (1), sideritoflavone (2), 8-methoxycirsilineol (3), and eupatilin (4), along with two neo-clerodane diterpenes, roseostachenone (8) and a new compound, 3α,4α-epoxyroseostachenol (7). In order to study structure-activity relationships, two methoxyflavones [5-demethyltangeretin (5) and tangeretin (6)] were synthesized by the methoxylation of xanthomicrol. The isolated compounds (1-4, 7, and 8) as well as the xanthomicrol semisynthetic derivatives (5 and 6) were evaluated for their binding affinity to the μ and δ opioid receptors. Xanthomicrol was the most potent binder to both μ and δ receptors, with a Ki value of 0.83 and 3.6 μM, respectively. Xanthomicrol administered intraperitoneally in mice at a dose of 80 mg/kg significantly reduced morphine-induced antinociception in the tail flick test. Our results suggested that xanthomicrol is a μ opioid receptor antagonist. Docking experiments were carried out to acquire a deeper understanding about important structural aspects of binding of xanthomicrol. In summary, these data suggest that xanthomicrol is a valuable structure for further development into a potential μ opioid receptor antagonist.
authors.affiliation: Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Parco Scientifico e Tecnologico , Pula, Cagliari, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ruiu
authors.forename: Nicola
authors.initials: N
authors.lastname: Anzani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Orrù
authors.forename: Costantino
authors.initials: C
authors.lastname: Floris
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Caboni
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Elias
authors.initials: E
authors.lastname: Maccioni
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.forename: Filippo
authors.initials: F
authors.lastname: Cottiglia
mesh_terms: D000818:Animals; D047309:Flavones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005419:Flavonoids; D051379:Mice; D015394:Molecular Structure; D009020:Morphine / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists*; D031366:Stachys / Q000737:chemistry*
chemical_list: D047309:Flavones; D005419:Flavonoids; D011957:Receptors, Opioid; C000595952:sideritoflavone; C462036:xanthomicrol; C045325:eupatilin; C570738:4',5-dihydroxy-3',6,7,8-tetramethoxyflavone; D009020:Morphine