Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5-HT6 receptor ligands with significant selectivity for D3 over D2 receptors

Bioorg Med Chem. 2017 Jan 1;25(1):38-52. doi: 10.1016/j.bmc.2016.10.010. Epub 2016 Oct 12.

Abstract

All clinically-used antipsychotics display similar affinity for both D2 (D2R) and D3 (D3R) receptors, and they likewise act as 5-HT2A receptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D3 and 5-HT6 (5-HT6R) receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R versus D2R and likewise recognize 5-HT6R. Starting from the high affinity 5-HT6R ligands I and II, we identified compounds 11a and 14b that behave as 5-HT6R ligands with significant selectivity for D3R over D2R.

Keywords: Antipsychotic; Benzocyclobutane; CNS receptors; Indole; Schizophrenia.

MeSH terms

  • Antipsychotic Agents / chemistry*
  • Antipsychotic Agents / pharmacology*
  • Dopamine Antagonists / chemistry
  • Dopamine Antagonists / pharmacology
  • Drug Design*
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology
  • Molecular Docking Simulation
  • Polycyclic Compounds / chemistry
  • Polycyclic Compounds / pharmacology
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3 / metabolism*
  • Receptors, Serotonin / metabolism*
  • Schizophrenia / drug therapy
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / pharmacology

Substances

  • Antipsychotic Agents
  • Dopamine Antagonists
  • Indoles
  • Polycyclic Compounds
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Receptors, Serotonin
  • Serotonin Antagonists
  • serotonin 6 receptor
  • benzocyclobutene