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.
Aaron M Bender  1  2 ,  Michael S Valentine  3 ,  Joshua A Bauer  4  5 ,  Emily Days  4 ,  Craig W Lindsley  1  2  5  6 ,  W David Merryman  3
Affiliations
  • 1. Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Franklin, Tennessee, USA.
  • 2. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
  • 3. Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.
  • 4. Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee, USA.
  • 5. Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA.
  • 6. Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
PMID: 36930852 DOI: 10.1089/adt.2022.116
Abstract

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.
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