A tacrine-tetrahydroquinoline heterodimer potently inhibits acetylcholinesterase activity and enhances neurotransmission in mice
| Autor: | Guangmiao Fu, Nancy Y. Ip, Choi Ying Ling, Fangyuan Kang, Fengzhi Yang, Peiran Sun, Lei Fu, Yueqing Hu, Fanny C.F. Ip, Fangzhou Xie, Kit Cheung |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Neurotransmission Synaptic Transmission Rats Sprague-Dawley chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery medicine Animals Cholinergic neuron Huperzine A Dose-Response Relationship Drug Molecular Structure Organic Chemistry General Medicine Acetylcholinesterase Rats Mice Inbred C57BL Molecular Docking Simulation chemistry Tacrine Butyrylcholinesterase Synaptic plasticity Quinolines Cholinergic Cholinesterase Inhibitors Acetylcholine medicine.drug |
| Zdroj: | European journal of medicinal chemistry. 226 |
| ISSN: | 1768-3254 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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