Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen

Assay Drug Dev Technol. 2023 Apr;21(3):89-96. doi: 10.1089/adt.2022.116. Epub 2023 Mar 17.


Antagonists of the serotonin receptor 2B (5-HT2B) have shown great promise as therapeutics for the treatment of pulmonary arterial hypertension, valvular heart disease, and related cardiopathies. Herein, we describe a high-throughput screen campaign that led to the identification of highly potent and selective 5-HT2B antagonists. Furthermore, selected compounds were profiled for their predicted ability to cross the blood-brain barrier. Two exemplary compounds, VU0530244 and VU0631019, were predicted to have very limited potential for brain penetration in human subjects, a critical profile for the development of 5-HT2B antagonists devoid of centrally-mediated adverse effects.

Keywords: 5-HT2B, pulmonary arterial hypertension; high-throughput screen; serotonin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Receptor, Serotonin, 5-HT2B*
  • Serotonin*


  • Serotonin
  • Receptor, Serotonin, 5-HT2B