Histamine H3 receptor and cholinesterases as synergistic targets for cognitive decline: Strategies to the rational design of multitarget ligands

Abstract

The role of histamine and acetylcholine in cognitive functions suggests that compounds able to increase both histaminergic and cholinergic neurotransmissions in the brain should be considered as promising therapeutic options. For this purpose, dual inhibitors of histamine H₃ receptors (H₃ R) and cholinesterases (ChEs) have been designed and assessed. In this context, this paper reviews the strategies used to obtain dual H₃ R/ChEs ligands using multitarget design approaches. Hybrid compounds designed by linking tacrine or flavonoid motifs to H₃ R antagonists were obtained with high affinity for both targets, and compounds designed by merging the H₃ R antagonist pharmacophore with known anticholinesterase molecules were also reported. These reports strongly suggest that key modifications in the lipophilic region (including a second basic group) seem to be a strategy to reach novel compounds, allied with longer linker groups to a basic region. Some compounds have already demonstrated efficacy in memory models, although the pharmacokinetic and toxicity profile should be considered when designing further compounds. In conclusion, the key features to be considered when designing novel H₃ R/ChEs inhibitors with improved pharmacological profile were herein summarized.

Keywords: cholinesterase; designed multiple ligands; dual-target compounds; histamine H3 receptor; multitarget approach; procognitive agents.