2. Academic Validation
  3. Structure-Based Design of a Chemical Probe Set for the 5-HT5A Serotonin Receptor

Structure-Based Design of a Chemical Probe Set for the 5-HT5A Serotonin Receptor

  • J Med Chem. 2022 Mar 10;65(5):4201-4217. doi: 10.1021/acs.jmedchem.1c02031.
Anat Levit Kaplan 1,  Ryan T Strachan 2,  Joao M Braz 3,  Veronica Craik 3,  Samuel Slocum 4,  Thomas Mangano 4,  Vanessa Amabo 4,  Henry O'Donnell 1,  Parnian Lak 1,  Allan I Basbaum 3,  Bryan L Roth 2 4 5,  Brian K Shoichet 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94143, United States.
  • 2 Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 27514, United States.
  • 3 Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, United States.
  • 4 National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 27514, United States.
  • 5 Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 27514, United States.
PMID: 35195401 DOI: 10.1021/acs.jmedchem.1c02031
Abstract

The 5-HT5A receptor (5-HT5AR), for which no selective agonists and a few antagonists exist, remains the least understood serotonin receptor. A single commercial antagonist, SB-699551, has been widely used to investigate the 5-HT5AR function in neurological disorders, including pain, but this molecule has substantial liabilities as a chemical probe. Accordingly, we sought to develop an internally controlled probe set. Docking over 6 million molecules against a 5-HT5AR homology model identified 5 mid-μM ligands, one of which was optimized to UCSF678, a 42 nM arrestin-biased partial agonist at the 5-HT5AR with a more restricted off-target profile and decreased assay liabilities versus SB-699551. Site-directed mutagenesis supported the docked pose of UCSF678. Surprisingly, analogs of UCSF678 that lost the 5-HT5AR activity revealed that 5-HT5AR engagement is nonessential for alleviating pain, contrary to studies with less-selective ligands. UCSF678 and analogs constitute a selective probe set with which to study the function of the 5-HT5AR.

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