Please use this identifier to cite or link to this item: https://ninho.inca.gov.br/jspui/handle/123456789/5607
Title: CNS-selective noncompetitive cholinesterase inhibitors derived from the natural piperidine alkaloid (−)-spectalin
Authors: Castro, Newton Gonçalves de
Costa, Rodrigo Saar da
Pimentel, Luísa Sá Barreto
Danuello, Amanda
Romeiro, Nelilma Correia
Viegas Junior, Claudio
Barreiro, Eliezer Jesus de Lacerda
Fraga, Carlos Alberto Manssour
Bolzani, Vanderlan da Silva
Rocha, Monica Santos
Keywords: Acetilcolinesterase
Acetylcholinesterase
Doença de Alzheimer
Alzheimer Disease
Teste do Labirinto Aquático de Morris
Morris Water Maze Test
Acetilcolinesterasa
Enfermedad de Alzheimer
Prueba del Laberinto Acuático de Morris
Issue Date: 2008
Publisher: European Journal of Pharmacology
Citation: CASTRO, Newton Gonçalves de et al. CNS-selective noncompetitive cholinesterase inhibitors derived from the natural piperidine alkaloid (−)-spectaline. European Journal of Pharmacology, v. 580, p. 339–349, 2008.
Abstract: LASSBio-767 [(−)-3-O-acetyl-spectaline] and LASSBio-822 [(−)-3-O-tert-Boc-spectaline] were recently described as cholinesterase inhibitors derived from the natural piperidine alkaloid (−)-spectaline, obtained from the flowers of Senna spectabilis (Fabaceae). We investigated their mechanism of inhibition of acetylcholinesterase and their efficacy in reversing scopolamine-induced amnesia. Competition assays with the substrate acetylthiocholine showed a concentration-dependent reduction in rat brain cholinesterase Vmax without changes in apparent Km. The kinetic data for LASSBio-767 and LASSBio-822 were best fit by a model of simple linear noncompetitive inhibition with Ki of 6.1 μM and 7.5 μM, respectively. A dilution assay showed a fast and complete reversal of inhibition, independent of incubation time. Simulated docking of the compounds into the catalytic gorge of Torpedo acetylcholinesterase showed interactions with the peripheral anionic site, but not with the catalytic triad. Anti-amnestic effects in mice were assessed in a step-down passive avoidance test and in the Morris water maze 30 min after injection of scopolamine (1 mg/kg i.p.). Saline, LASSBio-767, or LASSBio-822 was administered 15 min before scopolamine. Both compounds reversed the scopolamine-induced reduction in step-down latency at 0.1 mg/kg i.p. LASSBio-767 reversed scopolamine-induced changes in water maze escape latency at 1 mg/kg i.p. or p.o., while its cholinergic side effects were absent or mild up to 30 mg/kg i.p. (LD50 above 100 mg/kg i.p.). Thus, the (−)-spectaline derivatives are potent cholinergic agents in vivo, with a unique profile combining noncompetitive cholinesterase inhibition and CNS selectivity, with few peripheral side effects.
Description: p. 339–349.: il. p&b.
URI: http://sr-vmlxaph03:8080/jspui/handle/123456789/5607
ISSN: 0014-2999
Appears in Collections:Artigos de Periódicos da área de Farmácia



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