Synthesis and biological evaluation of thioadatanserin and its dialkylated products as partial 5-HTR 1A agonists and 5-HTR 2A antagonists for potential use in depression and anxiety disorders

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127358. doi: 10.1016/j.bmcl.2020.127358. Epub 2020 Jun 17.


Thionation of adatanserin hydrochloride (2) with Lawesson's reagent in toluene/triethylamine afforded novel compound, (3r,5r,7r)-N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)adamantane-1-carbothioamide (thioadatanserin, 3) in 84-90% isolated yield. Thioadatanserin underwent a tandem double alkylation with methyl iodide and benzyl bromide in NaH/THF to produce novel dialkylated products 6 and 7 respectively. The single X-ray crystal structure of 7 was determined to be 1-(2-((E- ((3r,5r,7r)-adamantan-1-yl)benzylthio)methylene)amino)ethyl)-1-benzyl-4- (pyrimidin-2-yl)piperazin-1-ium bromide showing that the piperazine ring adopts a chair-like configuration that is not co-planar with the pyrimidine ring. Thioadatanserin emerged as a dual potent partial agonist with activity against 5-HTR1A (EC50 6.7 nM) and antagonist activity against 5-HTR2A (IC50 62.3 nM) and was selective over 5-HTR2C receptor (IC50 > 3333 nM) in the PathHunter® β-arrestin assays.

Keywords: 5-HTR(1A) partial agonist; 5-HTR(2A) antagonist; Adatanserin; Tandem alkylation; Thioadatanserin; Thionation; β-arrestin.

MeSH terms

  • Alkylation
  • Anxiety Disorders / drug therapy*
  • Depression / drug therapy*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / chemical synthesis
  • Serotonin 5-HT1 Receptor Agonists / chemistry
  • Serotonin 5-HT1 Receptor Agonists / pharmacology*
  • Serotonin 5-HT2 Receptor Antagonists / chemical synthesis
  • Serotonin 5-HT2 Receptor Antagonists / chemistry
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology*
  • Structure-Activity Relationship


  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • Receptor, Serotonin, 5-HT1A