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

J Pharmacol Exp Ther. 1997 Mar;280(3):1261-9.


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.

MeSH terms

  • Acetylcholinesterase / drug effects
  • Animals
  • Benzazepines / pharmacology*
  • Biogenic Monoamines / metabolism
  • Butyrylcholinesterase / drug effects
  • Choline / metabolism
  • Choline O-Acetyltransferase / metabolism
  • Cholinesterase Inhibitors / pharmacology*
  • Learning / drug effects
  • Male
  • Memory / drug effects
  • Norepinephrine / metabolism*
  • Rats
  • Rats, Wistar
  • Receptors, Cholinergic / metabolism
  • Serotonin / metabolism*
  • Tacrine / pharmacology


  • Benzazepines
  • Biogenic Monoamines
  • Cholinesterase Inhibitors
  • Receptors, Cholinergic
  • Serotonin
  • Tacrine
  • TAK 147
  • Choline O-Acetyltransferase
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Choline
  • Norepinephrine