Design, synthesis and pharmacological evaluation of indolylsulfonamide amines as potent and selective 5-HT₆ receptor antagonists

Abstract

A series of N′-[3-(indole-1-sulfonyl) aryl]-N,N-dimethyl ethane-1,2-diamines and N′-[3-(indole-1-sulfonyl) aryl]-N,N-dimethyl propane-1,3-diamines was designed and synthesized as 5-HT₆ receptor ligands. These compounds, when screened in a functional reporter gene-based assay, displayed potent antagonistic activity with K_b values in the range of 1.8–60 nM. The lead compound 9y has shown good ADME surrogate properties, acceptable pharmacokinetic profile and is active in animal models of cognition like novel object recognition test and Morris water maze. It was selected for detailed profiling.

• 5-Hydroxytryptamine₆ receptor
• central nervous system
• cognition
• novel object recognition test
• structure activity relationship
• water maze

Acknowledgements

The support received from Discovery Analytical, DMPK, In vitro, In vivo departments and Mr Venkateswarlu Jasti, CEO, Suven Life Sciences Ltd., Hyderabad, India is gratefully acknowledged.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.