Discovery of a lead series of potent benzodiazepine 5-HT2C receptor agonists with high selectivity in functional and binding assays

Bioorg Med Chem Lett. 2020 Mar 1;30(5):126929. doi: 10.1016/j.bmcl.2019.126929. Epub 2019 Dec 26.

Abstract

A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2CR agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.

Keywords: 5-HT(2C) receptor; Agonist; GPCR; Lead identification.

MeSH terms

  • Animals
  • Benzodiazepines / chemical synthesis
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacokinetics
  • Benzodiazepines / pharmacology*
  • Dogs
  • Drug Discovery
  • Drug Stability
  • Heterocyclic Compounds, 3-Ring / chemical synthesis
  • Heterocyclic Compounds, 3-Ring / metabolism
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Macaca fascicularis
  • Male
  • Mice
  • Microsomes / metabolism
  • Molecular Structure
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / chemical synthesis
  • Serotonin 5-HT2 Receptor Agonists / metabolism
  • Serotonin 5-HT2 Receptor Agonists / pharmacokinetics
  • Serotonin 5-HT2 Receptor Agonists / pharmacology*
  • Structure-Activity Relationship

Substances

  • Heterocyclic Compounds, 3-Ring
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists
  • Benzodiazepines