Rationally designed N-phenylsulfonylindoles as a tool for the analysis of the non-basic 5-HT₆R ligands binding mode

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• The serotonin 6 receptor (5-HT₆R) is a target for neurological disorders.
• Non-basic ligands exhibit unexpected high affinity and selectivity for 5-HT₆R, a phenomenon lacking explanation.
• Existing research has not elucidated the binding mechanism of these non-basic compounds.

Purpose of the Study:

• To investigate the structural basis for the high affinity and selectivity of non-basic ligands at the 5-HT₆R.
• To design and synthesize novel non-basic analogs of known 5-HT₆R ligands.
• To understand the minimum structural requirements for effective binding to 5-HT₆R.

Main Methods:

• Rational design and synthesis of 42 novel 5-HT₆R ligand analogs.
• Measurement of binding affinity for 5-HT₆R and selectivity profiling against related receptors (5-HT_1AR, 5-HT_2AR, 5-HT₇R, D₂R).
• Computational studies including induced fit docking and molecular dynamics simulations.

Main Results:

• A simple N-phenylsulfonylindole (1e) displayed moderate affinity (K_i = 159 nM) for 5-HT₆R, suggesting minimal features are sufficient for binding.
• No specific interactions were identified as solely responsible for the activity of non-basic compounds.
• Highly active non-basic compounds (3e, 5g) with K_i values of 65 nM and 38 nM, respectively, showed increased affinity with additional functional groups.

Conclusions:

• Ligand binding to 5-HT₆R can be driven by conformation with minimal structural features.
• Additional functional groups can enhance binding affinity through further interactions.
• This study provides a foundation for developing simpler, highly selective 5-HT₆R ligands.