title: CNS-selective noncompetitive cholinesterase inhibitors derived from the natural piperidine alkaloid (-)-spectaline.
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 microM and 7.5 microM, 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.
authors: Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, CCS Bloco J Sala J1-029, 21941-902, Rio de Janeiro, RJ, Brazil. ngcastro@farmaco.ufrj.br
authors: Newton G
authors: NG
authors: Castro
authors: Rodrigo S
authors: RS
authors: Costa
authors: Luisa S B
authors: LS
authors: Pimentel
authors: Amanda
authors: A
authors: Danuello
authors: Nelilma C
authors: NC
authors: Romeiro
authors: Cláudio
authors: C
authors: Viegas
authors: Eliezer J
authors: EJ
authors: Barreiro
authors: Carlos A M
authors: CA
authors: Fraga
authors: Vanderlan S
authors: VS
authors: Bolzani
authors: Monica S
authors: MS
authors: Rocha
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000284:Administration, Oral; D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000201:enzymology; D002384:Catalysis / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007700:Kinetics; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000633:toxicity; D013028:Space Perception / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: C487262:3-O-acetylspectaline; C529173:3-O-tert-butoxycarbonylspectaline; D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D015507:Drugs, Investigational; D010880:Piperidines; C480880:spectaline; D012601:Scopolamine; D000110:Acetylcholinesterase