Dual cholinergic modulation in dementia : quinuclidine carbamates targeting butyrylcholinesterase and α7 nicotinic receptor

Mastnak-Sokolov, Peter (author), Knez, Damijan (author), Meden, Anže (author), Strašek Benedik, Nika (author), Ferjančič Benetik, Svit (author), Hrast Rambaher, Martina (author), Zorman, Maša (author), Gobec, Stanislav (author)

Alzheimer's disease (AD) is the leading cause of dementia worldwide, but current therapies provide only symptomatic relief. Multi-target directed ligands (MTDLs) represent a promising approach to address AD pathology by modulating multiple targets with a single molecule. Here we describe quinuclidine carbamates that act simultaneously on butyrylcholinesterase (BChE) and the cholinergic α7 nicotinic receptor (α7 nAChR), thereby approaching cholinergic dysfunction at two levels: by modulating acetylcholine degradation and by direct agonism at this receptor. Starting with the α7 nAChR agonist bradanicline, its amide group was replaced by a carbamate moiety to enhance BChE inhibition while retaining receptor agonism. These quinuclidine carbamates inhibited BChE in the submicromolar range with the desired selectivity over acetylcholinesterase (AChE). In a calcium-flux assay on recombinant HEK293T cells expressing the α7 nAChR, all compounds were agonists of the α7 nAChR in the nanomolar range. Importantly, compound 6b displayed balanced, submicromolar activity against both targets. The crystal structures confirmed non-covalent binding to the active site of human BChE, and the 6b-hBChE complex also revealed an unprecedented flip of Tyr440, representing the first described example of backdoor opening for hBChE. Taken together, these results demonstrate that quinuclidine carbamates are promising dual modulators of hBChE and α7 nAChR, supporting their potential as MTDLs for AD therapy and highlighting this underexplored dual-target strategy as a promising approach in cholinergic drug discovery.

• Language: English
• Keywords: Alzheimer's disease, butyrylcholinesterase, human α7 nicotinic receptor, α7 nAChR, multi-target-directed ligands, quinuclidine carbamates, acetylcholine receptor, cholinergic receptor
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: 15 str.
• Numbering: Vol. 423, art. 111830
• PID: 20.500.12556/RUL-182778
• UDC: 615.2:616.892.3
• ISSN on article: 1872-7786
• DOI: 10.1016/j.cbi.2025.111830
• COBISS.SI-ID: 259409923
• Publication date in RUL: 22.05.2026

Record is a part of a journal

• Title: Chemico-biological interactions
• Publisher: Elsevier
• ISSN: 1872-7786
• COBISS.SI-ID: 23211013

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: Alzheimerjeva bolezen, butirilholinesteraza, človeški nikotinski receptor α7, α7 nAChR, večciljni usmerjeni ligandi, kinuklidinske karbamate, acetilholinski receptor, holinergični receptor, zdravila, demenca