title: Neurochemical effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-b enzazepin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase inhibitor, in rats.
abstract: We examined the neurochemical effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzaze pin-8-yl)-1-propanone fumarate (TAK-147), a novel acetylcholinesterase (AChE) inhibitor in vitro and in vivo. TAK-147 showed a potent and reversible inhibition of AChE activity in homogenates of the rat cerebral cortex (IC50 = 51.2 nM), and was 3.0- and 2.4-fold more potent than tacrine and physostigmine, respectively. By contrast, TAK-147 was the least potent inhibitor of butyrylcholinesterase activity in rat plasma (IC50 = 23,500 nM). Tacrine and physostigmine inhibited butyrylcholinesterase activity potently and nonselectively. TAK-147 showed a moderate inhibition of muscarinic M1 and M2 receptor binding with K(i) values of 234 and 340 nM, respectively. TAK-147 showed very weak or no inhibition of high-affinity choline uptake, nicotinic receptor binding and choline acetyltransferase activity. In ex vivo experiments, oral administration of TAK-147 at doses ranging from 1 to 10 mg/kg induced a statistically significant and dose-dependent decrease in AChE activity in the cerebral cortex. Of the monoaminergic systems, TAK-147 moderately inhibited uptake of noradrenaline and serotonin with IC50 values of 4020 and 1350 nM, respectively. TAK-147 also inhibited ligand binding at alpha-1, alpha-2 and serotonin 2 receptors with K(i) values of 324, 2330 and 3510 nM, respectively, whereas it showed only weak activities on D1, D2 and serotonin 1A receptor bindings. Oral administration of TAK-147 (3 mg/kg) significantly accelerated the turnover rates of dopamine, noradrenaline and serotonin in the rat brain. These results suggest that TAK-147 activates the central cholinergic system by specific inhibition of AChE activity without affecting peripheral butyrylcholinesterase activity, and that TAK-147 also moderately activates the monoaminergic systems.
authors.affiliation: Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hirai
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Nakayama
authors.forename: H
authors.initials: H
authors.lastname: Hayako
authors.forename: Y
authors.initials: Y
authors.lastname: Ishihara
authors.forename: G
authors.initials: G
authors.lastname: Goto
authors.forename: M
authors.initials: M
authors.lastname: Miyamoto
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011950:Receptors, Cholinergic / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013619:Tacrine / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D015306:Biogenic Monoamines; D002800:Cholinesterase Inhibitors; D011950:Receptors, Cholinergic; D012701:Serotonin; D013619:Tacrine; C099872:TAK 147; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002794:Choline; D009638:Norepinephrine