Syntheses of chalcone derivatives and evaluation of their affinities for mu opioid receptors

J. HIGGS; CRISTINA WASOWSKI; MARIEL MARDER

Buenos Aires

Jornada; . Official World Congress of Pain Satellite Meeting hosted by The Pain and Pain Management in Non-Human Species Special Interest Group; 2014

IASP

Introduction: Flavonoids are members of a class of natural compounds with considerable scientific and therapeutic interest. A number of chalcones (1,3-diaryl-2-propen-1-ones) and their derivatives have been found to inhibit the synthesis of the major proinflamatory mediators (nitric oxide and prostaglandins) that remain the most targeted pathways for antiinflammatory and antinociceptive drug development. Despite the existence of an immense number of reports showing significant antiinflammatory effects of chalcones, very few have explored their antinociceptive effects or their affinities to central nervous system receptors related to pain. Previous studies from our laboratory demonstrated the capacity of a series of flavonoids (synthetic and natural flavonoid glycosides and aglycones) to bind to the mu opioid receptor. The most active compound was the synthetic flavonoid 3,3-dibromoflavanone which presented a significant inhibition of the binding of the selective mu opioid ligand [3H] DAMGO, with a Ki of 0.846 ± 0.263 µM. In acute chemical and thermal models of nociception in mice, it exerted a dose dependent antinociceptive effect and showed no sedative, anxiolytic, motor incoordination effects or inhibition of the gastrointestinal transit at the doses tested. Blockade in vivo assays revealed that mu opioid receptors seem to be involved in its mechanism of action. Moreover, distinctive side effects of morphine such as constipation, tolerance and hypo/hyperlocomotion were not present after chronic administration of 3,3-dibromoflavanone in mice.   Aim: Synthesize chalcones, open chain flavonoids, as the previous step to obtain flavanones, and study their capacity to bind to mu opioid receptors.   Methods: The synthesis was performed by condensation of the appropriate acetophenone and benzaldehyde in the presence of aqueous bases. All the compoundswere purified and identified by mass spectrometry, 1H-NMR and 13C-NMR spectroscopy. The affinity of these compounds to bind to mu opioid receptors present in rat forebrain membranes was evaluated by their capacity to inhibit the binding of [3H] DAMGO.   Results:  A series of chalcone derivatives were synthesized and evaluated in competitive binding assays. The affinities of the active compounds ranged from 13 μM to 90 μM. OMe and OH substitutionsat the 4?-position impairs this effect, while the rest of the substitutions on the ring A of thechalcone nucleus seems not significantly affect receptor binding. The 5?-methyl-2?-hydroxy-3-nitrochalcone presented the best affinity (Ki= 13.5 ± 6.9 μM).   Conclusions: Flavonoid derivatives are opioid ligands that could be emerging as novel analgesics. The next step in our research is to evaluate the in vivo effect of the most active chalcones and perform their cyclization to obtain flavanones.