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Pathway-selective 5-HT1AR agonist as a rapid antidepressant strategy.

Chunyu Wang1, Nan Zhang1, Yujie Shao1

  • 1Institute of Health and Medicine, Hefei Comprehensive National Science Center; State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Cell
|November 13, 2025
PubMed
Summary

New research reveals how serotonin 5-HT1AR receptors signal differently. Targeting specific pathways with novel agonists like TMU4142 offers a promising strategy for developing faster-acting antidepressants.

Keywords:
5-HT(1A)RG(i/o) subtype selectivityantidepressantautoreceptorsdrug discoveryfeedback inhibitionheteroreceptorsligand recognitionstructural pharmacology

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Area of Science:

  • Neuropharmacology
  • Molecular Biology
  • Structural Biology

Background:

  • Presynaptic 5-HT1AR autoreceptors use Gi3, inhibiting antidepressant efficacy.
  • Postsynaptic 5-HT1AR heteroreceptors use Go, promoting antidepressant responses.
  • Selective activation of heteroreceptors over autoreceptors is challenging.

Purpose of the Study:

  • To characterize Gi/o subtype signaling profiles of 5-HT1AR.
  • To determine the structures of 5-HT1AR in complex with agonists and Gi/o proteins.
  • To elucidate mechanisms of agonist recognition and Gi/o signaling selectivity.

Main Methods:

  • Gi/o subtype signaling profile characterization.
  • X-ray crystallography for structural determination.
  • Functional assays for agonist activity and pathway selectivity.
  • Antidepressant-like effect assessment in a mouse model.

Main Results:

  • Detailed structural and functional analysis of 5-HT1AR-Gi/o interactions.
  • Identification of distinct agonist recognition modes and Gi/o signaling selectivity.
  • Design and validation of TMU4142, a pathway-selective agonist (high GoA, low Gi3).
  • TMU4142 demonstrated rapid antidepressant-like effects in vivo.

Conclusions:

  • Distinct Gi/o signaling pathways differentiate 5-HT1AR autoreceptors and heteroreceptors.
  • Targeting these distinct pathways is a viable strategy for developing rapid-acting antidepressants.
  • TMU4142 represents a promising lead compound for novel antidepressant therapies.