Acetylcholine neurotransmission is thought to be important in combating Alzheimer’s disease. When acetylcholine transmission is reduced, cognitive impairment as seen in Alzheimer’s patients is observed. Therefore, maintaining or increasing the level of acetylcholine in the brain is the strategy to treat this disease.
There are two known enzymes that catalytically hydrolyze acetylcholine in the brain. These are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). AChE is the predominant enzyme, while BChE is thought to have a supportive role. Because of that, AChE inhibition has traditionally been the goal to set. However, as the disease progresses, it is noted that AChE levels progressively decrease while BChE levels increase. Eventually BChE becomes the more abundant enzyme. As such, at later stages of the disease, the more effective battle may be against BChE.
Another strategy is to use a molecule that acts as inhibitor for both AChE and BChE. Rivastigmine is such a dual inhibitor and is currently used in treatment of dementia. However, rivastigmine is more selective for AChE than BChE. Another molecule, bambuterol, is more selective for BChE than AChE. Therefore, a hybrid analogue molecule of rivastigmine and bambuterol may have improved potency and selectivity than either molecule alone.
To test this idea, 15 hybrids were synthesized and evaluated in vitro for their capability as AChE and BChE inhibitors. As it turns out, each of these hybrids is a stronger inhibitor of BChE than bambuterol. One of them also had longer-lasting inhibition. These hybrids are a good starting point in searching for new candidates for Alzheimer’s research.
Wu J, Tan Z, Pistolozzi M, et al. Rivastigmine-bambuterol hybrids as selective butyrylcholinesterase inhibitors. Molecules. 2023 Dec 22;29(1). doi: 10.3390/molecules29010072. PMID: 38202655