Cholinesterase inhibitory activity of chlorophenoxy derivatives-Histamine H3 receptor ligands

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4140-5. doi: 10.1016/j.bmcl.2016.04.054. Epub 2016 Apr 20.

Abstract

In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both enzymes (EeAChE IC50=1.93μM and EqBuChE IC50=1.64μM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases.

Keywords: Acetylcholinesterase inhibitors; Butyrylcholinesterase inhibitors; Chlorophenoxy derivatives; Histamine H3 receptor; Multifunctional ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism*
  • Amines / chemistry*
  • Binding Sites
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism*
  • Catalytic Domain
  • Cholinesterase Inhibitors / chemistry*
  • Humans
  • Kinetics
  • Ligands
  • Molecular Docking Simulation
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Receptors, Histamine H3 / chemistry
  • Receptors, Histamine H3 / metabolism*
  • Structure-Activity Relationship

Substances

  • 1-(7-(4-chlorophenoxy)heptyl)homopiperidine
  • Amines
  • Cholinesterase Inhibitors
  • Ligands
  • Piperidines
  • Receptors, Histamine H3
  • Acetylcholinesterase
  • Butyrylcholinesterase