Dual Histamine H_3R/Serotonin 5?HT4R Ligands with Antiamnesic Properties: Pharmacophore-Based Virtual Screening and Polypharmacology

摘要

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 H_3R 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 Me?dicament 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 (H_3R Ki = 41.6 nM; 5-HT_4R 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 H_3R and 5-HT4R activities in a single molecule, raising the exciting possibility that dual H_3R antagonist/5HT_4R agonist have potential for the treatment of neurodegenerative diseases such as Alzheimer's disease.