Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer’s Disease Mouse Model

We present the synthesis and characterization of merged
human butyrylcholinesterase
(hBChE) inhibitor/cannabinoid receptor 2 (hCB2R) ligands for the treatment of neurodegeneration.
In total, 15 benzimidazole carbamates were synthesized and tested
for their inhibition of human cholinesterases, also with regard to
their pseudoirreversible binding mode and affinity toward both cannabinoid
receptors in radioligand binding studies. After evaluation in a calcium
mobilization assay as well as a β-arrestin 2 (βarr2) recruitment
assay, two compounds with balanced activities on both targets were
tested for their immunomodulatory effect on microglia activation and
regarding their pharmacokinetic properties and blood–brain
barrier penetration. Compound 15d, containing a dimethyl
carbamate motif, was further evaluated in vivo, showing prevention
of Aβ25–35-induced learning impairments in
a pharmacological mouse model of Alzheimer’s disease for both
short- and long-term memory responses. Additional combination studies
proved a synergic effect of BChE inhibition and CB2R activation
in vivo.