Comparison of the antinociceptive activity of two new NO-releasing derivatives of the NSAID S-ketoprofen in rats.

1 Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes inducing analgesic, anti-inflammatory and antipyretic actions. They are not devoid of severe side effects and so, the search for new compounds with similar or higher effectiveness and a lower incidence of undesired actions is important. Nitric oxide (NO)-releasing NSAIDs resulted from this search. 2 We have compared the antinociceptive effectiveness of cumulative doses of two new NO-releasing derivatives of S-ketoprofen, HCT-2037 and HCT-2040, using the recording of spinal cord nociceptive reflexes in anesthetized and awake rats and after intravenous and oral administration. 3 S-ketoprofen and HCT-2040 were equieffective in reducing responses to noxious mechanical stimulation after i.v. administration in anesthetized animals (ID50s: 1.3+/-0.1 and 1.6+/-0.2 micromol kg(-1) respectively), but did not modify wind-up. HCT-2037 was two-fold more potent (ID50 of 0.75+/-0.1 micromol kg(-1)) in responses to mechanical stimuli and very effective in reducing wind-up (63+/-17% of control; P<0.01; MED: 0.4 micromol kg(-1)), indicating a greater activity than the parent compound. 4 In awake animals with inflammation, HCT-2037 p.o. fully inhibited mechanical allodynia, 91+/-12% reduction, and hyperalgesia, 94+/-8% reduction. Equivalent doses of S-ketoprofen only partially reduced either allodynia (50+/-11%) or hyperalgesia (40+/-4%). The effect on responses to noxious thermal stimulation was similar for the two compounds. 5 We conclude that the molecular changes made in the structure of S-ketoprofen including an NO moiety in its structure, improve the antinociceptive profile of the compound opening new perspectives in a safer use of NSAIDs as analgesic drugs.