Reichau_2026_ACS.Chem.Neurosci__

Alzheimer's disease (AD) remains an incurable neurodegenerative disorder, requiring novel therapeutic strategies. We developed multitarget-directed 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 inhibitor 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, respectively. 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 the lipopolysaccharide-induced pro-inflammatory activation profile in 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 Abeta(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.