Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer's disease

Aminobenzimidazoles and Structural Isomers as Templates for Dual‐Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders

“…Our knowledge about the orientation of pharmacophores for BChE inhibitors led to the observation that the pharmacophore model also applies to: 1) the benzimidazole‐based CB 2 R agonist described by AstraZeneca (Figure ) that we had used as parent ligand in the preparation of bivalent CB 2 R ligands, and 2) the dual‐acting ligand described by González‐Naranjo et al. (Figure ) . There was a recent report on (unselective) ChE inhibitors based on a benzimidazole core, adding further support to the hypothesis that such benzimidazoles might inhibit ChEs …”

“…In a second work, CB 2 R agonists with BChE‐inhibitory properties were prepared and investigated. Although the best compounds showed only moderate affinities (mostly in the two‐digit micromolar range), and selectivity at the CBRs and ChEs were not pronounced, this study has very valuable explorative character and is the first to achieve such a dual‐acting compound.…”

“…Several preliminary efforts into the development of multifunctional CBR ligands have been described: In an initial work, the combination of a CB 1 R antagonist with the AChE inhibitor tacrine in the form of a hybrid molecule was achieved . In a second work, CB 2 R agonists with BChE‐inhibitory properties were prepared and investigated.…”

“… Simplified pharmacophore model (pharmacophores circled) of a prototypical competitive BChE inhibitor A and application of this model on a recently described dual‐acting compound with an indazole ether scaffold ( B ) and on a CB 2 R‐selective ligand described by AstraZeneca ( C ) …”

Rational Modification of the Biological Profile of GPCR Ligands through Combination with Other Biologically Active Moieties

“…There are several examples in which GPCR affinity was merged with enzyme inhibition in one molecule in bi‐functional compounds, such as adenosine A 2A affinity and MAO‐B inhibition , or CB 2 R affinity and cholinesterase (ChE) inhibition . In the following section, we describe the combination of ChE inhibition with antagonism at the histamine receptor subtype 3 (H 3 R).…”