A tacrine-tetrahydroquinoline heterodimer potently inhibits acetylcholinesterase activity and enhances neurotransmission in mice

Eur J Med Chem. 2021 Dec 15:226:113827. doi: 10.1016/j.ejmech.2021.113827.

Fanny C F Ip ¹, Guangmiao Fu ², Fengzhi Yang ³, Fangyuan Kang ², Peiran Sun ², Choi Ying Ling ², Kit Cheung ², Fangzhou Xie ³, Yueqing Hu ², Lei Fu ⁴, Nancy Y Ip ⁵

Affiliations

1 Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, China; Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, Shenzhen-Hong Kong Institute of Brain Science, HKUST Shenzhen Research Institute, Shenzhen, Guangdong, 518057, China.
2 Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
3 School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
4 School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China. Electronic address: leifu@sjtu.edu.cn.
5 Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, China; Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, Shenzhen-Hong Kong Institute of Brain Science, HKUST Shenzhen Research Institute, Shenzhen, Guangdong, 518057, China. Electronic address: boip@ust.hk.

PMID: 34530383 DOI: 10.1016/j.ejmech.2021.113827

Abstract

Cholinergic neurons are ubiquitous and involved in various higher brain functions including learning and memory. Patients with Alzheimer's disease exhibit significant dysfunction and loss of cholinergic neurons. Meanwhile, such cholinergic deficits can be potentially relieved pharmacologically by increasing acetylcholine. Acetylcholinesterase (AChE) inhibitors have been used to improve cholinergic transmission in the brain for two decades and have proven effective for alleviating symptoms in the early stages of Alzheimer's disease. Therefore, the search for AChE inhibitors for drug development is ongoing. The enzymatic pocket of AChE has long been the target of several drug designs over the last two decades. The peripheral and catalytic sites of AChE are simultaneously bound by several dimeric molecules, enabling more-efficient inhibition. Here, we used 6-chlorotacrine and the tetrahydroquinolone moiety of huperzine A to design and synthesize a series of heterodimers that inhibit AChE at nanomolar potency. Specifically, compound 7b inhibits AChE with an IC₅₀ < 1 nM and spares butyrylcholinesterase. Administration of 7b to mouse brain slices restores synaptic activity impaired by pirenzepine, a muscarinic M1-selective antagonist. Moreover, oral administration of 7b to C57BL/6 mice enhances hippocampal long-term potentiation in a dose-dependent manner and is detectable in the brain tissue. All these data supported that 7b is a potential cognitive enhancer and is worth for further exploration.

Keywords

Cognitive function; Dementia; Electrophysiological recordings; Hybrid; Synaptic plasticity.

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