Evaluation of γ-carboline-phenothiazine conjugates as simultaneous NMDA receptor blockers and cholinesterase inhibitors

Bioorg Med Chem. 2021 Sep 15:46:116355. doi: 10.1016/j.bmc.2021.116355. Epub 2021 Aug 8.

Abstract

Alzheimer's disease (AD) is the most common form of dementia. It is associated with the impairment of memory and other cognitive functions that are mainly caused by progressive defects in cholinergic and glutamatergic signaling in the central nervous system. Inhibitors of acetylcholinesterase (AChE) and ionotropic glutamate receptors of the N-methyl-d-aspartate (NMDA) receptor family are currently approved as AD therapeutics. We previously showed using a cell-based assay of NMDA receptor-mediated glutamate-induced excitotoxicity that bis-γ-carbolinium conjugates are useful NMDA receptor blockers. However, these compounds also act as subnanomolar AChE inhibitors, which may cause serious anticholinergic side effects when applied in vivo. Here, we evaluated new structures containing γ-carbolines linked to phenothiazine via a propionyl spacer. These compounds were superior to the previously characterized bis-γ-carbolinium conjugates because they blocked NMDA receptors without requiring a quaternary pyridine N-atom and inhibited AChE with moderate IC50 values of 0.54-5.3 µM. In addition, these new compounds displayed considerable selectivity for the inhibition of butyrylcholinesterase (BChE; IC50 = 0.008-0.041 µM), which may be favorable for AD treatment. Inhibitory activities towards the NMDA receptors and AChE were in the same micromolar range, which may be beneficial for equal dosing against multiple targets in AD patients.

Keywords: AChE; Alzheimer’s disease; BChE; Carboline; Multitarget ligand; NMDA receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Butyrylcholinesterase / metabolism
  • Carbolines / chemistry
  • Carbolines / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Phenothiazines / chemistry
  • Phenothiazines / pharmacology*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Structure-Activity Relationship

Substances

  • Carbolines
  • Cholinesterase Inhibitors
  • Neuroprotective Agents
  • Phenothiazines
  • Receptors, N-Methyl-D-Aspartate
  • gamma-carboline
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • phenothiazine