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 H 3 receptors (H 3 R) and cholinesterases (ChEs) have been designed and assessed. In this context, this paper reviews the strategies used to obtain dual H 3 R/ChEs ligands using multitarget design approaches. Hybrid compounds designed by linking tacrine or flavonoid motifs to H 3 R antagonists were obtained with high affinity for both targets, and compounds designed by merging the H 3 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 H 3 R/ChEs inhibitors with improved pharmacological profile were herein summarized.

Evaluation of the histamine H3 receptor antagonists from LINS01 series as cholinesterases inhibitors: Enzymatic and modeling studies

“…The general approach to develop compounds with pro‐cognitive activity must rely on the activation of areas and pathways related to increased cognitive effect, and also avoid interfering with those related to cognitive loss. In order to interfere with several biological processes at the same time, the multitarget design, which is based on the “one drug, several targets” paradigm (Lopes et al, 2021), should be considered to discover compounds against complex diseases such as dementias.…”

“…It is involved in several CNS processes including feeding and sleeping regulation, hormonal homeostasis and cognitive functions indeed (Brown et al, 2001; Panula & Nuutinen, 2013; Provensi et al, 2020). All the four histamine receptors (H 1 R‐H 4 R) are expressed in the CNS, but the most explored as drug target to cognitive dysfunctions is the H 3 R, due to its expression as pre‐synaptic auto and hetero‐receptor (Lopes et al, 2021; Nieto‐Alamilla et al, 2016). This means that H 3 R may control the production and release of histamine and other neurotransmitters, being a very attractive target to treat narcolepsy, obesity, ADHD, drug addiction and several other CNS conditions.…”

“…Compound LINS01004 ( 2a ) was already assessed on a discriminative avoidance model of memory, being comparable to clobenpropit (widely studied H 3 R antagonist) and donepezil (drug approved to treat cognitive disorders, Figure 1; Soliani et al, 2020). However, the evident similarity between the structure of LINS01 compounds and donepezil (comprehended by an aromatic moiety, basic group and additional lipophilic substituent, Figure 1) inspired us to explore pharmacophore merging strategies to identify the potential of LINS01 compounds as dual targeted molecules to H 3 R and cholinesterases (ChEs), since these dual agents present important potential to cognitive dysfunctions as recently reviewed (Lopes et al, 2021). Considering this, the aim of this work was to assess the inhibitory activity of selected H 3 R ligands from LINS01 compounds against acetylcholinesterase (AChE).…”

“…However, no data were reported for these compounds as ChEs inhibitors until the present work. Considering the potential that dual H 3 R/ChEs ligands present against cognitive disorders (Lopes et al, 2021), these H 3 R antagonists were screened as ee AChE inhibitors (Table 1).…”

“…The clinical importance of BChE inhibition is frequently debated in literature, and it is suggested that inhibition of BChE plays important role when the AChE activity is low or absent due to massive neurodegeneration in Alzheimer's disease (Holmes et al, 2005; Li et al, 2008). It is important to remember that AChE is a neuronal enzyme, while BChE is mainly expressed in glial cells (Lopes et al, 2021; Tago et al, 1992), and thus the BChE activity may compensate the absence of AChE activity to hydrolyze ACh in later‐stages of AD. Therefore, compounds with inhibitory activity on BChE have also potential to produce pharmacological effect in such situation.…”