Department of Pharmaceutical Sciences, Universidade Federal de São Paulo, São Paulo, Brazil.
Chem Biol Drug Des. 2021 Aug;98(2):212-225. doi: 10.1111/cbdd.13866. Epub 2021 Jun 21.
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 receptors (H R) and cholinesterases (ChEs) have been designed and assessed. In this context, this paper reviews the strategies used to obtain dual H R/ChEs ligands using multitarget design approaches. Hybrid compounds designed by linking tacrine or flavonoid motifs to H R antagonists were obtained with high affinity for both targets, and compounds designed by merging the H 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 R/ChEs inhibitors with improved pharmacological profile were herein summarized.
组胺和乙酰胆碱在认知功能中的作用表明，能够增加大脑中组胺能和胆碱能神经传递的化合物应被视为有前途的治疗选择。为此，设计并评估了组胺 H 受体（H R）和胆碱酯酶（ChE）的双重抑制剂。在这方面，本文综述了使用多靶标设计方法获得双重 H R/ChE 配体的策略。通过将他克林或黄酮类化合物基序连接到 H R 拮抗剂上设计出的杂合化合物对这两个靶点均具有高亲和力，并且还报道了通过将 H R 拮抗剂药效团与已知的抗胆碱酯酶分子融合而设计出的化合物。这些报道强烈表明，在亲脂区域（包括第二个碱性基团）进行关键修饰似乎是一种获得新型化合物的策略，同时与碱性区域的较长连接基团相结合。一些化合物已经在记忆模型中显示出疗效，尽管在设计进一步的化合物时应考虑药代动力学和毒性特征。总之，本文总结了设计具有改善的药理特性的新型 H R/ChE 抑制剂时需要考虑的关键特征。
