9sl9
Structure of recombinant human butyrylcholinesterase in complex with (2S, 3R)-2-(pyridin-3-ylmethyl)quinuclidin-3-yl phenylcarbamate
Structural highlights
DiseaseCHLE_HUMAN Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:177400. BChE deficiency is a metabolic disorder characterized by prolonged apnoea after the use of certain anesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anesthetics. The duration of the prolonged apnoea varies significantly depending on the extent of the enzyme deficiency. BChE deficiency is a multifactorial disorder. The hereditary condition is transmitted as an autosomal recessive trait. FunctionCHLE_HUMAN Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.[1] [2] Publication Abstract from PubMedAlzheimer'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 alpha7 nicotinic receptor (alpha7 nAChR), thereby approaching cholinergic dysfunction at two levels: by modulating acetylcholine degradation and by direct agonism at this receptor. Starting with the alpha7 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 alpha7 nAChR, all compounds were agonists of the alpha7 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 alpha7 nAChR, supporting their potential as MTDLs for AD therapy and highlighting this underexplored dual-target strategy as a promising approach in cholinergic drug discovery. Dual cholinergic modulation in dementia: Quinuclidine carbamates targeting butyrylcholinesterase and alpha7 nicotinic receptor.,Mastnak-Sokolov P, Knez D, Meden A, Strasek Benedik N, Ferjancic Benetik S, Hrast Rambaher M, Zorman M, Nachon F, Brazzolotto X, Jardemark K, Jungholm O, Bruton J, Strandback E, Nyman T, Shahid M, Gobec S Chem Biol Interact. 2025 Nov 15;423:111830. doi: 10.1016/j.cbi.2025.111830. PMID:41242410[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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