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.
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.
Miyamoto
M
M
Pharmaceutical Research Laboratories I, Takeda Chemical Industries Ltd., Osaka, Japan.
Takahashi
H
H
Kato
K
K
Hirai
K
K
Ishihara
Y
Y
Goto
G
G
D000110:Acetylcholinesterase / Q000187:drug effects*; D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007858:Learning / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013619:Tacrine / Q000494:pharmacology
D001552:Benzazepines; D013619:Tacrine; C099872:TAK 147; D000110:Acetylcholinesterase; D003975:Diazepam