Papers of the Week

Hydrogen sulfide (HS) is a gaseous mediator that modulates several physiological and pathological processes. Phthalimide analogues, substances that have the phthalimide ring in the structure, belong to the group of thalidomide analogues. Both HS donors and phthalimide analogues exhibit activities in models of inflammation and pain. As molecular hybridization is an important strategy aiming to develop drugs with a better pharmacological profile, in the present study we synthesized a novel HS-releasing phthalimide hybrid, 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3-thione (PTD-HS), and evaluated its activity in models of inflammatory pain in mice. Per os (p.o.) administration of PTD-HS (125 or 250 mg/kg) reduced mechanical allodynia induced by carrageenan and lipopolysaccharide. Intraperitoneal (i.p.) administration of PTD-HS (25 mg/kg), but not equimolar doses of its precursors 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (14.2 mg/kg) and 2-phthalimidethanol (12 mg/kg), reduced mechanical allodynia induced by lipopolysaccharide. The antiallodynic effect induced by PTD-HS (25 mg/kg, i.p.) was more sustained than that induced by the HS donor NaHS (8 mg/kg, i.p.). Previous administration of hydroxocobalamin (300 mg/kg, i.p.) or glibenclamide (40 mg/kg, p.o.) attenuated PTD-HS antiallodynic activity. In conclusion, we synthesized a novel HS-releasing phthalimide hybrid and demonstrated its activity in models of inflammatory pain. PTD-HS activity may be due to HS release and activation of ATP-sensitive potassium channels. The demonstration of PTD-HS activity in models of pain stimulates further studies aiming to evaluate HS-releasing phthalimide hybrids as candidates for analgesic drugs.