Targeting neuroinflammation by activation of the sigma-1 receptor (S1R) and inhibition of butyrylcholinesterase (hBChE) leads to highly potent anti-amnesic compounds in an Alzheimer's disease mouse model

ABSTRACT Alzheimer's disease (AD) is a neurodegenerative disorder for which no effective preventative or curative treatment has yet been identified. Due to the multifactorial nature and complex pathophysiology of the disease, we developed a multi-target ligand that both inhibits human butyrylcholinesterase ( h BChE), a key enzyme linked to β-amyloid plaque formation, and activates the sigma-1 receptor (S1R), which modulates neuroinflammatory and protective pathways. To this end, a series of isoindolines were designed and synthesized, and their biological activity was evaluated. The most promising compound, 7c , exhibited significant dual activity, achieving nanomolar IC 50 values against h BChE and potent S1R activation. Subsequent in vivo studies in an Aβ 25-35 mouse model revealed an improvement in cognitive deficits in both short- and long-term memory at an effective dose of 0.01 mg/kg in WT Swiss-OF1 mice. This dose is 10-fold lower compared to single-target compounds 7a and 7b of this isoindoline series. The lack of neuroprotective effects in BChE knock-out (KO) mice confirmed the involvement of BChE inhibition for compounds 7c effects in WT mice. Further combinatorial studies employing a two-drug combination demonstrated synergy in the neuroprotective effect of the two targets.