CNS-selective noncompetitive cholinesterase inhibitors derived from the natural piperidine alkaloid (−)-spectaline

摘要: Abstract LASSBio-767 [(−)-3- O -acetyl-spectaline] and LASSBio-822 - tert -Boc-spectaline] were recently described as cholinesterase inhibitors derived from the natural piperidine alkaloid (−)-spectaline, obtained flowers of Senna spectabilis (Fabaceae). We investigated their mechanism inhibition acetylcholinesterase efficacy in reversing scopolamine-induced amnesia. Competition assays with substrate acetylthiocholine showed a concentration-dependent reduction rat brain V max without changes apparent K m . The kinetic data for best fit by model simple linear noncompetitive i 6.1 μM 7.5 μM, respectively. A dilution assay fast complete reversal inhibition, independent incubation time. Simulated docking compounds into catalytic gorge Torpedo interactions peripheral anionic site, but not triad. Anti-amnestic effects mice assessed step-down passive avoidance test Morris water maze 30 min after injection scopolamine (1 mg/kg i.p.). Saline, LASSBio-767, or was administered 15 min before scopolamine. Both reversed latency at 0.1 mg/kg i.p. escape 1 mg/kg p.o., while its cholinergic side absent mild up to 30 mg/kg (LD 50 above 100 mg/kg Thus, (−)-spectaline derivatives are potent agents vivo, unique profile combining CNS selectivity, few effects.