Lead identification of acetylcholinesterase inhibitors–histamine H3 receptor antagonists from molecular modeling

Currently, the only clinically effective treatment for Alzheimer’s disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H3 receptor antagonist. Both histamine H3 receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H3 antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies 2 indicate the peripheral anionic site (PAS) of AChE interacts with the β-amyloid (βA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of βA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor–histamine H3 receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.

The proposed binding mode for a novel acetylcholinesterase inhibitor–histamine H3 receptor antagonist is shown in the active site of acetylcholinesterase.Figure optionsDownload as PowerPoint slide