Premium
Multitarget‐Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H 3 R Antagonism for Neurodegenerative Diseases
Author(s) -
BautistaAguilera Óscar M.,
Hagenow Stefanie,
PalominoAntolin Alejandra,
FarréAlins Víctor,
Ismaili Lhassane,
Joffrin PierreLouis,
Jimeno María L.,
Soukup Ondřej,
Janočková Jana,
Kalinowsky Lena,
Proschak Ewgenij,
Iriepa Isabel,
Moraleda Ignacio,
Schwed Johannes S.,
Romero Martínez Alejandro,
LópezMuñoz Francisco,
Chioua Mourad,
Egea Javier,
Ramsay Rona R.,
MarcoContelles José,
Stark Holger
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201706072
Subject(s) - monoamine oxidase , histamine , neuroprotection , pharmacology , pharmacophore , monoamine neurotransmitter , chemistry , antagonism , monoamine oxidase b , cholinesterase , histamine h3 receptor , in vitro , receptor , biochemistry , biology , enzyme , agonist , serotonin
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 in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood–brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg −1 i.p.) also significantly improved lipopolysaccharide‐induced cognitive deficits.