title: In vitro binding affinities of a series of flavonoids for μ-opioid receptors. Antinociceptive effect of the synthetic flavonoid 3,3-dibromoflavanone in mice.
abstract: The pharmacotherapy for the treatment of pain is an active area of investigation. There are effective drugs to treat this problem, but there is also a need to find alternative treatments free of undesirable side effects. In the present work the capacity of a series of flavonoids to bind to the μ opioid receptor was evaluated. The most active compound, 3,3-dibromoflavanone (31), a synthetic flavonoid, presented a significant inhibition of the binding of the selective μ opioid ligand [(3)H]DAMGO, with a Ki of 0.846 ± 0.263 μM. Flavanone 31 was further synthesized using a simple and cheap procedure with good yield. Its in vivo effects in mice, after acute treatments, were studied using antinociceptive and behavioral assays. It showed no sedative, anxiolytic, motor incoordination effects or inhibition of the gastrointestinal transit in mice at the doses tested. It evidenced antinociceptive activity on the acetic acid-induced nociception, hot plate and formalin tests (at 10 mg/kg and 30 mg/kg). The results showed that the 5-HT2 receptor and the adrenoceptors seem unlikely to be involved in its antinociceptive effects. Naltrexone, a nonselective opioid receptors antagonist, totally blocked compound 31 antinociceptive effects on the hot plate test, but naltrindole (δ opioid antagonist) and nor-binaltorphimine (κ opioid antagonist) did not. These findings demonstrated that 3,3-dibromoflavanone (31), at doses that did not interfere with the motor performance, exerted clear dose dependent antinociception when assessed in the chemical and thermal models of nociception in mice and it seems that its action is related to the activation of the μ opioid receptor.
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (C1113AAD), 1113 Buenos Aires, Argentina. jhiggs@qb.ffyb.uba.ar
authors.forename: Josefina
authors.initials: J
authors.lastname: Higgs
authors.forename: Cristina
authors.initials: C
authors.lastname: Wasowski
authors.forename: Leonardo M
authors.initials: LM
authors.lastname: Loscalzo
authors.forename: Mariel
authors.initials: M
authors.lastname: Marder
mesh_terms: D019342:Acetic Acid / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000493:pharmacokinetics; D044950:Flavanones / Q000494:pharmacology / Q000627:therapeutic use; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005772:Gastrointestinal Transit / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D014316:Tritium / Q000493:pharmacokinetics; D059265:Visceral Pain / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*
chemical_list: C586245:3,3-dibromoflavanone; D000700:Analgesics; D000701:Analgesics, Opioid; D044950:Flavanones; D005419:Flavonoids; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009271:Naltrexone; D019342:Acetic Acid