Antinociceptive profile of 2,3,6-trisubstituted piperidine alkaloids: 3-O-acetyl-spectaline and semi-synthetic derivatives of (-)-spectaline.
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| Abstract |
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 micromol/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 ED(50) value of 56.6 micromol/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.
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| Authors | Cláudio Viegas Jr, Magna Suzana Alexandre-Moreira, Carlos Alberto Manssour Fraga, Eliezer Jesus Barreiro, Vanderlan da Silva Bolzani, Ana Luísa Palhares de Miranda |
| Journal | Chemical & pharmaceutical bulletin (Chem Pharm Bull (Tokyo)) Vol. 56 Issue 4 Pg. 407-12 (Apr 2008) ISSN: 0009-2363 [Print] Japan |
| PMID | 18379082 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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