Vanilloids. 1. Analogs of capsaicin with antinociceptive and antiinflammatory activity.

As part of a program to establish structure-activity relationships for vanilloids, analogs of the pungent principle capsaicin, the alkyl chain portion of the parent structure (and related compounds derived from homovanillic acid) was varied. In antinociceptive and antiinflammatory assays (rat and mouse hot plate and croton oil-inflamed mouse ear), compounds with widely varying alkyl chain structures were active. Short-chain compounds were active by systemic administration in the assays mentioned above but they retained the high pungency and acute toxicity characteristic of capsaicin. In contrast, the long chain cis-unsaturates, NE-19550 (vanillyloleamide) and NE-28345 (oleylhomovanillamide), were orally active, less pungent, and less acutely toxic than capsaicin. The potential of these compounds as antiinflammatory/analgesic agents is discussed in light of recent data on the mechanism of action of vanilloids on sensory nerve fibers.

Anti-inflammatory pharmacology and mechanism of the orally active capsaicin analogs, NE-19550 and NE-28345.

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.

The antinociceptive effect and pharmacokinetics of olvanil following oral and subcutaneous dosing in the mouse.

Mice were tested for response latency on a 55 degrees C hot plate after subcutaneous (S.C.) or oral administration of olvanil (dose level 200 and 300 mg/kg, respectively). Only the S.C. injection of olvanil produced antinociception. A pharmacokinetics experiment with radiolabeled olvanil (200 mg/kg) was conducted to determine whether this antinociception difference was related to a difference in plasma concentration of olvanil following the two routes of administration. The results indicate that concentrations of radioactivity (olvanil plus metabolites) in plasma reach a peak higher and faster after oral dosing than after S.C. injection. However, the area under the concentration-time curve (AUC) for recovery of radioactivity was slightly higher after the S.C. injection than after the oral dose of olvanil. In contrast, intact olvanil is barely measurable (10 to 30 ng/g) in plasma following an oral dose but is present in high concentration (100 to 2000 ng/g) following S.C. injection. The AUC for olvanil was also higher following a S.C. dose. These data indicate that olvanil fails to produce antinociception after oral dosing in mice not due to lack of absorption, but because it undergoes first pass metabolism.