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 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.
Viegas
Cláudio
C
Laboratório de Fitoquímica e Química Medicinal, Departamento de Ciências Exatas, Universidade Federal de Alfenas, Alfenas, Brazil.
Alexandre-Moreira
Magna Suzana
MS
Fraga
Carlos Alberto Manssour
CA
Barreiro
Eliezer Jesus
EJ
Bolzani
Vanderlan da Silva
Vda S
de Miranda
Ana Luísa Palhares
AL
D019342:Acetic Acid; D000109:Acetylcholine; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D002351:Carrageenan; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D005557:Formaldehyde; D006358:Hot Temperature; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011930:Reaction Time; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C487262:3-O-acetylspectaline; D000700:Analgesics; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010880:Piperidines; C480880:spectaline; D005557:Formaldehyde; D009020:Morphine; D002351:Carrageenan; D000109:Acetylcholine; D019342:Acetic Acid; D007213:Indomethacin