J Chem Inf Model - Dual histamine H3R/serotonin 5-HT4R ligands with antiamnesic properties: pharmacophore-based virtual screening and polypharmacology.

Tópicos

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Resumo

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 M?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 (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.

Resumo Limpo

recent year preclin clinic studi generat consider interest develop histamin h receptor hr antagonist novel treatment degen disord associ impair cholinerg function identifi novel scaffold hr antagon common featurebas pharmacophor model develop use screen compound cermn centr detud et de recherch sur le mdicament de normandi chemic librari virtual hit gather cluster particular interest tricycl deriv also exhibit potent htr affin benzohnaphthyridin deriv show highest hr affin compound hr ki nm htr ki nm complet revers amnesi effect scopolamin mgkg spatial work memori experi first time demonstr feasibl combin hr htr activ singl molecul rais excit possibl dual hr antagonisthtr agonist potenti treatment neurodegen diseas alzheim diseas

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