Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile

J Med Chem. 2020 Oct 8;63(19):10946-10971. doi: 10.1021/acs.jmedchem.0c00814. Epub 2020 Sep 23.


Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium / metabolism
  • Cricetulus
  • Cyclic AMP / metabolism
  • Drug Design*
  • MAP Kinase Signaling System / drug effects*
  • Phosphorylation
  • Rats
  • Serotonin Receptor Agonists / adverse effects
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / pharmacology
  • Serotonin Receptor Agonists / therapeutic use*
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • beta-Arrestins / metabolism*


  • Serotonin Receptor Agonists
  • beta-Arrestins
  • Cyclic AMP
  • Calcium