Activities of 2-phthalimidethanol and 2-phthalimidethyl nitrate, phthalimide analogs devoid of the glutarimide moiety, in experimental models of inflammatory pain and edema.
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.
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Adriana M
AM
Godin
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Débora P
DP
Araújo
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Raquel R
RR
Menezes
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Ana Mercy S
AM
Brito
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Ivo S F
IS
Melo
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Giovanna M E
GM
Coura
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Darly G
DG
Soares
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Leandro F S
LF
Bastos
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Flávio A
FA
Amaral
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Lucas S
LS
Ribeiro
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Daiane
D
Boff
Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Julliana R A
JR
Santos
Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Daniel A
DA
Santos
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Mauro M
MM
Teixeira
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Ângelo
Â
de Fátima
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil.
Renes R
RR
Machado
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Pampulha CEP 31270-901, Belo Horizonte, MG, Brazil. Electronic address: mmcoelho@farmacia.ufmg.br.
Márcio M
MM
Coelho
D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D010797:Phthalimides / Q000737:chemistry / Q000627:therapeutic use*
D007656:Ketoglutaric Acids; D010797:Phthalimides; C037431:phthalimide; C057563:glutaramic acid; D002351:Carrageenan
2-Phthalimidethanol; 2-Phthalimidethyl nitrate; Inflammation; Pain; Phthalimide analogs; Thalidomide