Low-basicity 5-HT₇ Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol.

ABSTRACT: A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT₇ receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, K _{i 5-HT7} = 6 nM, EC₅₀ = 19 nM, 176-fold selectivity over 5-HT_1AR) and 1e (5-methoxy analogue, K _{i 5-HT7} = 30 nM, EC₅₀ = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (C_max = 2723 n

SUBMITTER: Hogendorf AS 

PROVIDER: S-EPMC5431432 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature