Based on the hypothesis that analgetic activity is a dissociable feature of the cannabinoid molecule, we examined modifications of the side chain, the phenolic moiety, and, most significantly, structures that lack the benzopyran functionality present in THC and (—)‐9‐nor‐9β‐hydroxyhexahydrocannabinol (HHC). A new grouping, the 1‐methyl‐4‐phenylbutyloxy C‐3 side chain, elaborates a unique lipopholic region. Replacement of the phenol substituent produced several derivatives which retain analgetic activity in the codeine potency range. Introduction of a weakly basic nitrogen at C‐5 and deletion of the axial methyl group in the B ring, two structural changes forbidden by traditional cannabinoid SAR, resulted in a unique family of benzoquinolines with potent analgetic activity. The prototype of this series, levonantradol, exhibits potent and stereospecific analgetic and antiemetic activity.
In animal antinociceptive tests responsive to non-steroidal anti-inflammatory drugs (NSAID), piroxicam is an extremely potent and effective analgetic at doses of 1--2 mg/kg p.o. In mice the plasma half-life and duration of analgetic action is short (t 1/2 = 1.7 h), unlike man, wherein piroxicam exhibits an exceptionally long duration of action (half-life 40--45 h). An excellent correlation is observed between plasma levels and analgetic activity in the writhing test in mice suggesting that piroxicam will exhibit potent and long-lasting analgetic activity in man.
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