| Literature DB >> 35195401 |
Anat Levit Kaplan1, Ryan T Strachan2, Joao M Braz3, Veronica Craik3, Samuel Slocum4, Thomas Mangano4, Vanessa Amabo4, Henry O'Donnell1, Parnian Lak1, Allan I Basbaum3, Bryan L Roth2,4,5, Brian K Shoichet1.
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.Entities:
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Year: 2022 PMID： 35195401 PMCID： PMC9116900 DOI： 10.1021/acs.jmedchem.1c02031
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039