Dual Histamine H3R/Serotonin 5-HT4R Ligands with Antiamnesic Properties: Pharmacophore-Based Virtual Screening and Polypharmacology

In recent years, preclinical and clinical studies have generated considerable interest in the development of histamine H-3 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 Medicament 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 5HT(4)R affinity. Benzo[h] [1,6]naphthyridine derivatives showed the highest H3R affinity, and compound 17 (H3R K-i = 41.6 nM; 5-HT4R K-i = 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/5HT(4)R agonist have potential for the treatment of neurodegenerative diseases such as Alzheimer's disease.