Carabaza A, Cabré F, García A M, Rotllan E, García M L, Mauleón D
R&D Department, Laboratorios Menarini S.A., Badalona, Spain.
Chirality. 1997;9(3):281-5. doi: 10.1002/(SICI)1520-636X(1997)9:3<281::AID-CHIR13>3.0.CO;2-J.
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.
尽管一直认为非甾体抗炎药（NSAIDs）的作用主要是其对局部前列腺素合成作用的结果，但越来越多的证据表明它们也可能发挥中枢镇痛作用。一些作者认为，抑制大脑中的前列腺素合成可能有助于镇痛作用。在大鼠脑片段和大鼠脑微粒体的环氧化酶制剂中研究了右酮洛芬氨丁三醇（对映体（+）-S-酮洛芬的氨丁三醇盐）对前列腺素合成的影响。还评估了（-）-R-对映体和外消旋混合物的作用。在37℃孵育10分钟后，大鼠脑片段中合成了显著水平的前列腺素F2α（PGF2α）。发现右酮洛芬是大鼠脑中这种PGF2α产生的有效抑制剂（IC50 = 6.2 nM），并且在1μM浓度下它完全抑制了PGF2α的产生。此外，右酮洛芬对PGF2α合成的抑制具有高度立体选择性，因为对映体（-）-R-酮洛芬的效力明显较低（IC50 = 294 nM）；对于这种对映体，即使在1μM等高浓度下，抑制率也不到60%。这些结果与在消旋酮洛芬及其对映体对大鼠脑微粒体环氧化酶活性的研究中获得的结果相关，其中右酮洛芬也立体选择性地抑制酶活性。右酮洛芬、（-）-R-酮洛芬和消旋酮洛芬的IC50值分别为3.5μM、45.3μM和5.8μM。上述结果可能与右酮洛芬在体内观察到的强效镇痛作用有关，该作用也是立体选择性的。综上所述，这些发现表明右酮洛芬对大鼠脑前列腺素合成的抑制可能至少部分与这种NSAID的镇痛作用有关。
