New selective acetylcholinesterase inhibitors designed from natural piperidine alkaloids.
Five new piperidine alkaloids were designed from natural (-)-3-O-acetyl-spectaline and (-)-spectaline that were obtained from the flowers of Senna spectabilis (sin. Cassia spectabilis, Leguminosae). Two semi-synthetic analogues (7 and 9) inhibited rat brain acetylcholinesterase, showing IC50 of 7.32 and 15.1 microM, and were 21 and 9.5 times less potent against rat brain butyrylcholinesterase, respectively. Compound 9 (1mg/kg, i.p.) was fully efficacious in reverting scopolamine-induced amnesia in mice. The two active compounds (7 and 9) did not show overt toxic effects at the doses tested in vivo.
Viegas
Cláudio
C
Laboratório de Avaliação e Síntese, de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, CP 68023, 21944-910, Rio de Janeiro, Brazil.
Bolzani
Vanderlan S
VS
Pimentel
Luísa S B
LS
Castro
Newton G
NG
Cabral
Rafael F
RF
Costa
Rodrigo S
RS
Floyd
Corinne
C
Rocha
Mônica S
MS
Young
Maria C M
MC
Barreiro
Eliezer J
EJ
Fraga
Carlos A M
CA
D000110:Acetylcholinesterase / Q000737:chemistry*; D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D035264:Flowers / Q000737:chemistry; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000633:toxicity; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000633:toxicity; D013329:Structure-Activity Relationship
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D010880:Piperidines; D010936:Plant Extracts; C032727:piperidine; D012601:Scopolamine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase