Effects of T-82, a new quinoline derivative, on cholinesterase activity and extracellular acetylcholine concentration in rat brain.
The effects of T-82 (2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo [3,4-b]quinolin-1-one hemifumarate), a new quinoline derivative, on acetylcholinesterase (AChE) activity and acetylcholine (ACh) release were compared with those of the well-known cholinesterase inhibitors tacrine and E2020. T-82, tacrine and E2020 all concentration-dependently inhibited AChE in rat brain homogenate (IC50 = 109.4, 84.2 and 11.8 nM, respectively). In addition, although tacrine strongly inhibited butyrylcholinesterase (BuChE), T-82 and E2020 showed only weak activity on BuChE in human plasma. In ex vivo experiments, intraperitoneal administration of T-82 at a dose of 30 mg/kg inhibited AChE activity in the hippocampus, frontal cortex and parietal cortex of rats. The effect of T-82 on the extracellular ACh concentration in rat brain was measured using in vivo microdialysis. T-82 at doses of 10 and 30 mg/kg, i.p. increased the extracellular ACh concentration in the hippocampus and striatum in a dose-dependent manner. These findings suggest that T-82 activates the central cholinergic system by selectively inhibiting AChE activity, while weakly affecting peripheral BuChE activity, and that T-82 increases the extracellular ACh concentration in the brain, which is followed by inhibited AChE activity.
Isoma
Kazuo
K
Central Research Laboratories, SSP Co., Ltd., Narita, Japan. Kazuo.Isomae@ssp.co.jp
Ishikawa
Masago
M
Ohta
Megumi
M
Ogawa
Yoichiro
Y
Hasegawa
Hiroshi
H
Kohda
Tadayuki
T
Kamei
Junzo
J
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D002802:Cholinesterases / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000494:pharmacology; D008297:Male; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012472:Salivation / Q000187:drug effects; D013619:Tacrine / Q000494:pharmacology; D013696:Temperature
D002800:Cholinesterase Inhibitors; D007189:Indans; D010640:Phenothiazines; D010880:Piperidines; D011804:Quinolines; C012635:T-82; D013619:Tacrine; D000077265:Donepezil; C037219:quinoline; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases; D000109:Acetylcholine