142851-93-2Relevant articles and documents
Central Cholinergic Agents. 6. Synthesis and Evaluation of 3--1-(2,3,4,5-tetrahydro-1H-benzazepin-8-yl)-1-propanones and Their Analogs as Central Selective Acetylcholinesterase Inhibitors
Ishihara, Yuji,Hirai, Keisuke,Miyamoto, Masaomi,Goto, Giichi
, p. 2292 - 2299 (1994)
In an attempt to find central selective acetylcholinesterase (AChE) inhibitors, 3--1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanones 9 and their analogs were designed on the basis of our working hypothesis of the enzyme's active site.These compounds were prepared by regioselective Fridel-Crafts acylation of 2,3,4,5-tetrahydro-1H-1-benzazepines and related nitrogen heterocycles as a key step.Most compounds showed potent inhibitory activities with IC50s in the 10-300 nM range.In order to estimate their central selectivities, we examined their effects on the apomorphine-induced circling behavior in rats with unilateral striatal lesions.Among compounds with potent AChE inhibition, 3--1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (9a, TAK-147) (IC50 of AChE inhibition = 97.7 nM) inhibited the circling behavior at 3 mg/kg po, in which it had no significant effect on peripheral cholinergic effects.This demonstrates that 9a has favorable central selectivity.Furthermore, 9a significantly ameliorated diazepam-induced passive avoidance deficit at 1 mg/kg po.The benzazepine derivative 9a was selected as a candidate for clinical evaluation.
