title: Dual histamine H3R/serotonin 5-HT4R ligands with antiamnesic properties: pharmacophore-based virtual screening and polypharmacology.
abstract: In recent years, preclinical and clinical studies have generated considerable interest in the development of histamine H3 receptor (H3R) antagonists as novel treatment for degenerative disorders associated with impaired cholinergic function. To identify novel scaffolds for H3R antagonism, a common feature-based pharmacophore model was developed and used to screen the 17,194 compounds of the CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie) chemical library. Out of 268 virtual hits which have been gathered in 34 clusters, we were particularly interested in tricyclic derivatives also exhibiting a potent 5HT4R affinity. Benzo[h][1,6]naphthyridine derivatives showed the highest H3R affinity, and compound 17 (H3R Ki = 41.6 nM; 5-HT4R Ki = 208 nM) completely reversed the amnesiant effect of scopolamine at 3 mg/kg in a spatial working memory experiment. For the first time we demonstrated the feasibility to combine H3R and 5-HT4R activities in a single molecule, raising the exciting possibility that dual H3R antagonist/5HT4R agonist have potential for the treatment of neurodegenerative diseases such as Alzheimer's disease.
authors.affiliation: Normandie Université , CS 14032 Caen Cedex 5, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Lepailleur
authors.forename: Thomas
authors.initials: T
authors.lastname: Freret
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lemaître
authors.forename: Michel
authors.initials: M
authors.lastname: Boulouard
authors.forename: François
authors.initials: F
authors.lastname: Dauphin
authors.forename: Antoine
authors.initials: A
authors.lastname: Hinschberger
authors.forename: Fabienne
authors.initials: F
authors.lastname: Dulin
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lesnard
authors.forename: Ronan
authors.initials: R
authors.lastname: Bureau
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D015195:Drug Design; D054828:Histamine H3 Antagonists / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D062105:Molecular Docking Simulation; D064798:Polypharmacology; D011485:Protein Binding; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D054828:Histamine H3 Antagonists; D008024:Ligands; D018100:Receptors, Histamine H3; D058828:Serotonin 5-HT4 Receptor Agonists; D054852:Small Molecule Libraries; D044422:Receptors, Serotonin, 5-HT4