However, pravadoline was found to exhibit unexpectedly strong analgesic effects, which appeared at doses ten times smaller than the effective anti-inflammatory dose and so could not be explained by its action as aCOX inhibitor. These effects were not blocked by opioidantagonists such asnaloxone,[1] and it was eventually discovered that pravadoline represented the first compound from a novel class ofcannabinoidagonists, the aminoalkylindoles.[2]
Pravadoline was never developed for use as an analgesic, partly due to toxicity concerns (although these were later shown to be a result of the salt form that the drug had been prepared in rather than from the pravadoline itself),[3] however the discovery of cannabinoid activity in this structurally novel family of drugs led to the discovery of several new cannabinoid agonists, including the drugWIN 55,212-2, which is now widely used in scientific research.[4][5]
Prevented thenociceptive response induced by paw flexion in theadjuvant-arthritic rat (ED50 41 mg/kg, p.o.)
Prevented the nociceptive response ofbradykinin-induced head and forepaw flexion (ED50 78 mg/kg, p.o.)
The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadoline-induced antinociception was not antagonized by naloxone (1 mg/kg, s.c.) and pravadoline did not bind to theopioid receptors at concentrations up to 10 μM.[1]
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