Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases

Angew Chem Int Ed Engl. 2017 Oct 2;56(41):12765-12769. doi: 10.1002/anie.201706072. Epub 2017 Sep 1.

Abstract

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg-1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

Keywords: antioxidants; drug design; inhibitors; multitarget drugs; neurological agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry*
  • Antioxidants / pharmacokinetics
  • Antioxidants / therapeutic use
  • Blood-Brain Barrier / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacokinetics
  • Cholinesterase Inhibitors / therapeutic use
  • Cognitive Dysfunction / drug therapy
  • Cognitive Dysfunction / metabolism
  • Drug Design
  • Histamine H3 Antagonists / chemical synthesis
  • Histamine H3 Antagonists / chemistry*
  • Histamine H3 Antagonists / pharmacokinetics
  • Histamine H3 Antagonists / therapeutic use
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacokinetics
  • Indoles / therapeutic use
  • Ligands
  • Mice
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry*
  • Monoamine Oxidase Inhibitors / pharmacokinetics
  • Monoamine Oxidase Inhibitors / therapeutic use
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry*
  • Neuroprotective Agents / pharmacokinetics
  • Neuroprotective Agents / therapeutic use
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacokinetics
  • Piperidines / therapeutic use

Substances

  • Antioxidants
  • Cholinesterase Inhibitors
  • Histamine H3 Antagonists
  • Indoles
  • Ligands
  • Monoamine Oxidase Inhibitors
  • N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine
  • Neuroprotective Agents
  • Piperidines