A Dual Approach To Combat Alzheimer's Disease through Concomitant hBChE Inhibition and S1R Activation
Résumé
Alzheimer's disease (AD) remains an incurable neurodegenerative disorder, requiring novel therapeutic strategies. We developed multitarget ligands designed to inhibit human butyrylcholinesterase (hBChE) and activate the sigma-1 receptor (S1R), addressing both cholinergic dysfunction and neuroinflammation, the latter being reduced through action on both targets. The (pseudo)-irreversible carbamate 18c emerged as the most promising compound, exhibiting potent and selective hBChE inhibition (IC 50 = 3.3 nM, 45-fold selectivity over human acetylcholinesterase) and strong S1R agonistic activity (IC 50 = 25 nM, EC 50 = 99 nM) determined in a radioligand binding assay and by S1R-BiP dissociation. Its cleavage product 14c (after carbamate hydrolysis by hBChE) retained dual activity (IC 50 (hBChE) = 269 nM, IC 50 (S1R) = 20 nM, and EC 50 (S1R) = 279 nM). Both compounds reduced lipopolysaccharide (LPS)-induced pro-inflammatory activation profile in the microglial N9 cells while preserving anti-inflammatory marker expression, thereby indicating an overall immunomodulatory effect. In vivo, inhibitor 18c improved cognitive deficits in a mouse model with Aβ 25-35 -induced neurotoxicity, enhancing short-and long-term memory in Y-maze and passive avoidance tests at dosages as low as 0.1-1 mg/kg. These findings highlight the potential of dual-targeting hBChE/S1R strategies for AD therapy.
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