Activities of 2-phthalimidethanol and 2-phthalimidethyl nitrate, phthalimide analogs devoid of the glutarimide moiety, in experimental models of inflammatory pain and edema

• Published in: Pharmacology, biochemistry and behavior Vol. 122; pp. 291 - 298
• Main Authors: Godin, Adriana M., Araújo, Débora P., Menezes, Raquel R., Brito, Ana Mercy S., Melo, Ivo S.F., Coura, Giovanna M.E., Soares, Darly G., Bastos, Leandro F.S., Amaral, Flávio A., Ribeiro, Lucas S., Boff, Daiane, Santos, Julliana R.A., Santos, Daniel A., Teixeira, Mauro M., de Fátima, Ângelo, Machado, Renes R., Coelho, Márcio M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2014
• Subjects: 2-Phthalimidethanol; 2-Phthalimidethyl nitrate; Animals; Carrageenan - toxicity; Disease Models, Animal; Edema - chemically induced; Edema - drug therapy; Edema - metabolism; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Ketoglutaric Acids - chemistry; Male; Mice; Mice, Inbred C57BL; Pain; Pain - drug therapy; Pain - metabolism; Pain Measurement - drug effects; Pain Measurement - methods; Phthalimide analogs; Phthalimides - chemistry; Phthalimides - therapeutic use; Thalidomide; Phthalimide analogs; Inflammation; Pain; 2-Phthalimidethanol; 2-Phthalimidethyl nitrate; Thalidomide
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2014.04.008

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 (300μg) induced mechanical allodynia and this response was inhibited by previous per os (p.o.) administration of PTD-OH and PTD-NO (750mg/kg) and also by thalidomide (500 or 750mg/kg). The edema induced by carrageenan was also inhibited by previous p.o. administration of PTD-OH (500 and 750mg/kg) and PTD-NO (125, 250, 500 or 750mg/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 (500mg/kg) reduced all the parameters, while PTD-OH (500mg/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 (500mg/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. •2-Phthalimidethanol and 2-phthalimidethyl nitrate reduce inflammatory pain and edema.•2-Phthalimidethyl nitrate reduces TNF-α and CXCL1 concentrations and MPO activity.•2-Phthalimidethyl nitrate increases nitrite concentrations.