title: Central cholinergic agents. 6. Synthesis and evaluation of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepi n-8-yl)-1-propanones and their analogs as central selective acetylcholinesterase inhibitors.
abstract: In an attempt to find central selective acetylcholinesterase (AChE) inhibitors, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1- benzazepin-8-yl)-1-propanones 9 and their analogs were designed on the basis of our working hypothesis of the enzyme's active site. These compounds were prepared by regioselective Friedel-Crafts acylation of 2,3,4,5-tetrahydro-1H-1-benzazepines and related nitrogen heterocycles as a key step. Most compounds showed potent inhibitory activities with IC50s in the 10-300 nM range. In order to estimate their central selectivities, we examined their effects on the apomorphine-induced circling behavior in rats with unilateral striatal lesions. Among compounds with potent AChE inhibition, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1- benzazepin-8-yl)-1-propanone fumarate (9a, TAK-147) (IC50 of AChE inhibition = 97.7 nM) inhibited the circling behavior at 3 mg/kg po, in which it had no significant effect on peripheral cholinergic effects. This demonstrates that 9a has favorable central selectivity. Furthermore, 9a significantly ameliorated diazepam-induced passive avoidance deficit at 1 mg/kg po. The benzazepine derivative 9a was selected as a candidate for clinical evaluation.
authors.affiliation: Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ishihara
authors.forename: K
authors.initials: K
authors.lastname: Hirai
authors.forename: M
authors.initials: M
authors.lastname: Miyamoto
authors.forename: G
authors.initials: G
authors.lastname: Goto
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D010277:Parasympathomimetics / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001552:Benzazepines; D002800:Cholinesterase Inhibitors; D010277:Parasympathomimetics; D003975:Diazepam