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We have evaluated the properties of a new class of anti-inflammatory agents derived from capsaicin, using the analogs NE-19550 (N-vanillyloleamide) and NE-28345 (N-oleyl-homovanillamide) as examples. This class displayed an atypical profile in the assays utilized, including 1) anti-edema and antileukocyte migration activity in the rat carrageenan pleurisy assay without suppression of pleural prostanoid synthesis, 2) blockade of human platelet aggregation induced by arachidonate or PAF but not that induced by the PGH2 analog U-46619, without equivalent inhibition in vitro of mammalian cyclooxygenase or thromboxane synthetase preparations, 3) greater potency and efficacy in the rat implanted sponge assay than in the adjuvant arthritis assay, without inhibition of LTB4 or 15-HETE synthesis in vitro, 4) stronger topical activity in the mouse croton oil inflamed ear assay than the guinea pig UV erythema assay, and 5) oral activity in the rat carrageenan paw edema assay and mouse phenylquinone abdominal constriction rest combined with failure to induce gastric erosion in rats at therapeutic doses. We conclude that NE-19550 and NE-28345 do not act like conventional NSAIDs via suppression of arachidonic acid metabolism.

NE-19550, N-(3-methoxy-4-hydroxybenzyl)oleamide, is a capsaicin analogue that has been shown to possess oral activity in the 55 degrees C rat hot-plate and mouse phenylquinone abdominal constriction analgesia tests. The compound also displayed anti-inflammatory activity orally in the carrageenan-inflamed rat-paw test and topically in the croton oil-inflamed mouse-ear test. NE-19550 activity in the thermal analgesia assay was not blocked by the opioid antagonist naloxone, and no inhibition of prostanoid synthesis in rat platelets or tissues was seen following a high analgesic and anti-inflammatory oral dose (300 mg/kg). A wide variety of known neuronal antagonists (adrenergic, serotonergic, dopaminergic, cholinergic, GABA-ergic, histaminergic) were found not to inhibit NE-19550 analgesia, further indicating a lack of involvement of known drug receptors mediating analgesic responses. Analgesic doses of NE-19550 were also found to lack the acute toxicity and thermoregulatory desensitization characteristics of the parent natural product capsaicin. It appears to represent a new class of potent-acting, non-narcotic, anti-inflammatory analgesic agents.