Effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1 - H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase inhibitor, on impaired learning and memory in animal models

M Miyamoto, H Takahashi, K Kato, K Hirai, Y Ishihara and G Goto

Pharmaceutical Research Laboratories I, Takeda Chemical Industries Ltd., Osaka, Japan.

We examined the effects of p.o. administered 3-[1-(phenylmethyl)-4- piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-b enzazepin-8- yl)-1-propanone fumarate (TAK-147), a novel AChE inhibitor, on impaired learning and memory in animal models. At 1 to 3 mg/kg, TAK-147 ameliorated the passive avoidance deficit induced by diazepam. TAK-147 did not affect delayed-matching-to-position (DMTP) performance of normal rats at doses of 1 to 30 mg/kg assessed by using a three-lever operant chamber, but 9- amino-tetrahydroacridine disrupted the DMTP response at 5 to 20 mg/kg. Scopolamine (0.02-0.1 mg/kg s.c.) impaired DMTP performance, whereas methylscopolamine did not affect the DMTP task. TAK-147 ameliorated the impairment of DMTP performance induced by scopolamine without affecting the general behavior of the rats; however, 9-amino-tetrahydroacridine produced no significant amelioration of the impairment. The intraventricular injection of AF64A disrupted differential- reinforcement-of-low-rate 10-sec performance in rats, as demonstrated by marked decreases in reinforcement rate and response efficiency. TAK- 147 slightly increased the reinforcement rate in AF64A-treated rats at a low dose of 1 mg/kg, but the effect was not significant statistically. TAK-147 had no significant effect on the duration of immobility in rats in a forced swimming test at doses of 2 to 10 mg/kg. 9-Amino-tetrahydroacridine prolonged the duration of immobility at 5 to 20 mg/kg. Furthermore, TAK-147 reversed reserpine-induced hypothermia and ptosis in mice at doses of 3 to 10 mg/kg, a result that implies an antidepressant-like action. These results indicate that TAK-147 ameliorates learning and memory impairment in animal models without affecting the general behavior or causing behavioral depression and suggest that TAK-147 may be useful for the treatment of Alzheimer's disease.

Volume 277, Issue 3, pp. 1292-1304, 06/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

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