Antinociceptive Profile of 2,3,6-Trisubstituted Piperidine Alkaloids: 3-O-Acetyl-spectaline and Semi-synthetic Derivatives of (−)-Spectaline

In early studies, we have reported the antinociceptive profile of (−)-spectaline, a piperidine alkaloid from Cassia spectabilis. The present study describes the synthesis, the antinociceptive and anti-inflammatory activities of a series of 2,3,6-trialkyl-piperidine alkaloids: the natural (−)-3-O-acetyl-spectaline (LASSBio-755) and ten semi-synthetic spectaline derivatives. Structure–activity relationship (SARs) studies were performed. The structures of all synthesized derivatives were confirmed by means of nuclear magnetic resonance. Compounds were evaluated for their analgesic (acetic acid-induced mouse abdominal constrictions, hot-plate test, formalin-induced pain test) and some of them for the anti-inflammatory activities (carrageenan-induced rat paw edema test). The pharmacological results showed that several of the new compounds given orally at a dose of 100 μmol/kg significantly inhibited the acetic acid-induced abdominal constrictions, but they were less active than (−)-spectaline. LASSBio-755 and LASSBio-776 were the most actives with 37% and 31.7% of inhibition. In the formalin-induced pain only LASSBio-776 was able to inhibit by 34.4% the paw licking response of the inflammatory phase, (−)-spectaline and LASSBio-755 did show any activity. In the carrageenan-induced rat paw edema, only (−)-spectaline exhibited an anti-inflammatory profile, showing an ED50 value of 56.6 μmol/kg. Our results suggest different mechanisms of action for the analgesic activity observed for LASSBio-776 (3-O-Boc-spectaline), LASSBio-755 (3-O-acetyl-spectaline) and (−)-spectaline (LASSBio-754). The antinociceptive profile of some of the semi-synthetic spectaline derivatives extends our research concerning the chemical and pharmacological optimization of isolated natural products in the search of new drug candidates from brazilian biodiversity.