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

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-imid...

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Autores principales: Adam S. Hogendorf, Agata Hogendorf, Rafał Kurczab, Grzegorz Satała, Tomasz Lenda, Maria Walczak, Gniewomir Latacz, Jadwiga Handzlik, Katarzyna Kieć-Kononowicz, Joanna M. Wierońska, Monika Woźniak, Paulina Cieślik, Ryszard Bugno, Jakub Staroń, Andrzej J. Bojarski
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2017
Materias:
Medicine
R
Science
Q
Acceso en línea:https://doaj.org/article/b2815ce3d4e34da783160c0d85d688cb
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Sumario: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-HT1AR) 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 (Cmax = 2723 ng/g) were found for 1o after i.p. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT7R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT1AR selectivity.

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