20.500.12556/RUL-182778 Dual cholinergic modulation in dementia quinuclidine carbamates targeting butyrylcholinesterase and α7 nicotinic receptor 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. Alzheimer's disease butyrylcholinesterase human α7 nicotinic receptor α7 nAChR multi-target-directed ligands quinuclidine carbamates acetylcholine receptor cholinergic receptor Alzheimerjeva bolezen butirilholinesteraza človeški nikotinski receptor α7 α7 nAChR večciljni usmerjeni ligandi kinuklidinske karbamate acetilholinski receptor holinergični receptor zdravila demenca true false true Angleški jezik Slovenski jezik Članek v reviji 2026-05-22 14:12:48 2026-05-22 14:12:59 2026-05-23 04:42:00 0000-00-00 00:00:00 2026 0 0 15 str. art. 111830 Vol. 423 Jan. 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.2:616.892.3 1872-7786 10.1016/j.cbi.2025.111830 259409923 1-s2.0-S0009279725004600-main.pdf 1-s2.0-S0009279725004600-main.pdf 1 F431CFB2B91921FEE65AE1CA51040B10 f66d832f26f7a44093bcefce27027f183451dcc6dcd9e1e2c1eaeeac30a1e3d5 a6e092a7-55d7-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=234316 https://www.sciencedirect.com/science/article/pii/S0009279725004600 0 4107abe2-55d7-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=234315 Fakulteta za farmacijo 0 0 0