Synthesis and structure–activity relationship of novel conformationally restricted analogues of serotonin as 5-HT₆ receptor ligands

Abstract

5-Hydroxytryptamine 6 receptors (5-HT₆R) are being perceived as the possible target for treatment of cognitive disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structure–activity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and N-benzyl substituents as 5-HT₆ receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity at 5-HT₆R with the K_i of 23.4 and 20.5 nM, respectively. The lead compound from the series 15a has acceptable ADME properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task (NORT) and water maze.

Keywords::

• Heck reaction
• cognition
• NORT
• serotonin
• 5-HT₆

Acknowledgement

The authors wish to acknowledge the support received from Mr. Venkateswarlu Jasti, CEO, Suven Life Sciences Ltd., Hyderabad, India.

Declaration of interest

The authors report no declarations of interest.

Supporting information

Analytical data of rest of the compounds, protocols for Morris water maze test, NORT and CYP inhibition assay were given in the Supporting information.