Novel piperidine derivatives. Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives

Abstract

A series of 1-benzyl-4-[2-(N-benzoylamino)-ethyl]piperidine derivatives was synthesized and evaluated for antiacetylcholinesterase (anti-AChE) activity. Substituting the benzamide with a bulky moiety in the para position led to a substantial increase in activity. Introduction of an alkyl or phenyl group at the nitrogen atom of benzamide dramatically enhanced the activity. The basic quality of the nitrogen atom of piperidine appears to play an important role in the increased activity, since the N-benzoylpiperidine derivative was almost inactive. We found that 1-benzyl-4-[2-[N-[4''-(benzylsulfonyl)benzoyl]-N-methylamino]ethyl]piperidine hydrochloride (21) (IC50 = 0.56 nM) is one of the most potent inhibitors of acetylcholinesterase. Compound 21 showed an affinity 18000 times greater for AChE than for BuChE. At a dose of 3 mg/kg, 21 produced a marked and significant increase in acetylcholine (ACh) content in the cerebral vortex and hippocampus of rats. Compound 21 was chosen for advanced development as an antidementia agent.