The reintroduction of
thalidomide in the
pharmacotherapy greatly stimulated the interest in the synthesis and pharmacological evaluation of
phthalimide analogs with new and improved activities and also greater safety. In the present study, we evaluated the activities of two
phthalimide analogs devoid of the
glutarimide ring, namely
2-phthalimidethanol (PTD-
OH) and
2-phthalimidethyl nitrate (PTD-NO), in experimental models of inflammatory
pain and
edema in male C57BL/6J mice. Intraplantar (i.pl.) injection of
carrageenan (300 μg) induced
mechanical allodynia and this response was inhibited by previous per os (p.o.) administration of PTD-
OH and PTD-NO (750 mg/kg) and also by
thalidomide (500 or 750 mg/kg). The
edema induced by
carrageenan was also inhibited by previous p.o. administration of PTD-
OH (500 and 750 mg/kg) and PTD-NO (125, 250, 500 or 750 mg/kg), but not by
thalidomide.
Carrageenan increased
tumor necrosis factor (TNF)-α and CXCL1 concentrations and also the number of neutrophils in the paw tissue. Previous p.o. administration of PTD-NO (500 mg/kg) reduced all the parameters, while PTD-
OH (500 mg/kg) reduced only the accumulation of neutrophils.
Thalidomide, on the other hand, was devoid of effect on these biochemical parameters. Plasma concentrations of
nitrite were increased after p.o. administration of the
phthalimide analog coupled to a NO donor, PTD-NO (500 mg/kg), but not after administration of PTD-
OH or
thalidomide. In conclusion, our results show that small molecules, structurally much simpler than
thalidomide or many of its analogs under investigation, exhibit similar activities in experimental models of
pain and
inflammation. Finally, as there is evidence that the
glutarimide moiety contributes to the teratogenic effect of many
thalidomide analogs, our results indicate that
phthalimide analogs devoid of this functional group could represent a new class of
analgesic and anti-inflammatory candidates with potential greater safety.