Vol. 280, Issue 3, 1261-1269, 1997

Neurochemical Effects of 3-[1-(Phenylmethyl)-4-Piperidinyl]-1-(2,3,4,5-Tetrahydro-1H-1-Benzazepin-8-yl)-1-Propanone Fumarate (TAK-147), a Novel Acetylcholinesterase Inhibitor, in Rats

Keisuke Hirai, Koki Kato, Takahiro Nakayama, Hitomi Hayako, Yuji Ishihara, Giichi Goto and Masaomi Miyamoto

Pharmaceutical Research Laboratories I (K.H., K.K., T.N., H.H., Y.I., M.M.) and Research on Research (G.G.), Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka 532, Japan

We examined the neurochemical effects of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-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.