Stereoselective inhibition of rat brain cyclooxygenase by dexketoprofen.
Although it has been assumed that the effects of nonsteroidal antiinflammatory drugs (NSAIDs) are mainly the result of their action on local synthesis of prostaglandins, there is growing evidence to suggest that they may also exert a central analgesic action. Some authors have suggested that inhibition of prostaglandin synthesis in the brain could contribute to the analgesic action. The effect of dexketoprofen trometamol (tromethamine salt of the enantiomer (+)-S-ketoprofen) on prostaglandin synthesis was investigated in rat brain fragments and in cyclooxygenase preparations from rat brain microsomes. Effects of the (-)-R-enantiomer and the racemic mixture were also evaluated. Significant levels of prostaglandin F2 alpha (PGF2 alpha) were synthesized in rat brain fragments after 10 min of incubation at 37 degrees C. Dexketoprofen was found to be a potent inhibitor of this PGF2 alpha production in rat brain (IC50 = 6.2 nM), and it completely suppressed PGF2 alpha production at 1 microM concentration. In addition, inhibition of PGF2 alpha synthesis by dexketoprofen was highly stereoselective since the enantiomer (-)-R-ketoprofen was significantly less potent (IC50 = 294 nM); with this enantiomer, even at high concentrations such as 1 microM, less than 60% inhibition was achieved. These results correlated with those obtained in the study of racemic ketoprofen and its enantiomers on cyclooxygenase activity of rat brain microsomes, where dexketoprofen also inhibited enzymatic activity stereoselectively. IC50 values obtained for dexketoprofen, (-)-R-ketoprofen, and rac-ketoprofen were 3.5 microM, 45.3 microM, and 5.8 microM, respectively. The above results could be related to the potent analgesic effect of dexketoprofen observed in vivo, which was also stereoselective. Taken together, these findings suggest that prostaglandin synthesis inhibition in rat brain by dexketoprofen could be associated, at least in part, with the analgesic effect of this NSAID.
Carabaza
A
A
R&D Department, Laboratorios Menarini S.A., Badalona, Spain.
Cabré
F
F
García
A M
AM
Rotllan
E
E
García
M L
ML
Mauleón
D
D
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D001923:Brain Chemistry / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015237:Dinoprost / Q000378:metabolism; D066298:In Vitro Techniques; D007660:Ketoprofen / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D016861:Cyclooxygenase Inhibitors; D007660:Ketoprofen; D015237:Dinoprost; D011451:Prostaglandin-Endoperoxide Synthases