Atividades do 2-ftalimidoetanol e do nitrato de 2-ftalimidoetila, análogos ftalimídicos destituídos do anel glutarimídico, em modelos experimentais de dor e inflamação

Abstract

As phthalimide analogues interact with different molecular targets, there is an increasing interest in the evaluation of their potential as drug candidates in the treatment of patients with various diseases including those with inflammatory and painful manifestations. Furthermore, the development of phthalimide analogues coupled to a nitric oxide (NO) donor may result in drugs with high anti-inflammatory and antinociceptive activities. Thus, we aimed to characterize the effects induced by two phthalimide analogues devoid of the glutarimide moiety, 2-phthalimidethanol (FTD-OH) and 2-phthalimidethyl nitrate (FTD-NO), in experimental models of pain and inflammation in mice and to investigate the underlying mechanisms of action. There is increasing interest in phthalimide analogues devoid of the glutarimide moiety as the presence of this functional group has been shown to be associated with teratogenesis in preclinical assays. The phthalimide analogues, FTD-OH and FTD-NO, and thalidomide, used as a comparator drug, at the doses of 500 or 750 mg/kg (p.o., -1 h), inhibited the first and second phases of the nociceptive response induced by formaldehyde (1.84%, 20 µl, s.c.). Only the highest dose of the phthalimide analogues (750 mg/kg, p.o., -1 h) or the two highest doses (500 or 750 mg/kg, p.o., -1 h) of thalidomide inhibited the mechanical allodynia induced by carrageenan (300 µg, 20 µl, i.pl.). The two phthalimide analogues FTD-OH and FTD-NO (125, 250, 500 or 750 mg/kg, p.o., -1 h) also inhibited the paw edema induced by carrageenan or formaldehyde. Both phthalimide analogues (500 mg/kg, p.o., -1 h) reduced the activity of myeloperoxidase, but only FTD-NO (250 or 500 mg/kg, p.o., -1 h) reduced the concentrations of TNF- and CXCL1 in the paw of the animals injected with carrageenan. FTD-OH, FTD-NO and thalidomide (500 mg/kg, p.o., -1 h) inhibited the mechanical allodynia in the model of arthritis induced by antigen (mBSA). The two analogues (500 mg/kg, p.o., -1 h) also inhibited the cell migration and cytokine production induced by mBSA. In the model of mechanical allodynia induced by chronic constriction injury, treatments with both analogues or thalidomide (500 mg/kg, p.o., -1 h) were effective. Regarding the ability to increase the plasma concentration of nitrite, an indirect evidence of the production of NO, it was observed that only the analogue FTD-NO exhibited this activity. In addition, it was demonstrated that the antiedematogenic activity of the phthalimide analogues FTD-OH and FTD-NO involves cannabinoidergic and opioidergic mechanisms and activation of the guanylyl cyclase pathway. Prior administration of the CB1 (AM251, 8 mg/kg, i.p., -1.5 h) or opioid (naltrexone, 10 mg/kg, i.p. -1.5 h) receptor antagonists or the inhibitor of the enzyme guanylyl cyclase (ODQ, 8 mg/kg, p.o., -1.5 h) attenuated the antiedematogenic activity of the phthalimide analogues. Concluding, the results demonstrated the antinoceptive and anti-inflammatory activities of the phthalimide analogues FTD-OH and FTD-NO. The characterization of these activities indicates that the phthalimide analogues devoid of the glutarimide moiety represent a class that may be explored aiming the development of new drugs to be used in the treatment of patients with inflammatory and painful conditions. These results may also increase the interest in carrying out assays to evaluate the pre-clinical toxicological profiles of these analogues and their pharmacokinetic parameters, essential steps to the advance of research aiming the development of new pharmacotherapeutic alternatives.