Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases
Abstract
The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H-3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs.
These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional invitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier.
With this promising invitro profile, contilisant (at 1mgkg(-1) i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.