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

Chunyu Wang; Nan Zhang; Yujie Shao; Tao Li; Mengna Zhang; Meng Gao; Yaqi Liang; Yumeng Wang; Tian Xue; Yiming Shi; He Chen; Can Cao

doi:10.1016/j.cell.2025.10.022

Pathway-selective 5-HT_1AR agonist as a rapid antidepressant strategy

Cell. 2025 Dec 11;188(25):7222-7237.e24. doi: 10.1016/j.cell.2025.10.022. Epub 2025 Nov 12.

Authors

Chunyu Wang¹, Nan Zhang², Yujie Shao², Tao Li³, Mengna Zhang², Meng Gao², Yaqi Liang³, Yumeng Wang², Tian Xue⁴, Yiming Shi⁵, He Chen⁶, Can Cao⁷

Affiliations

¹ Institute 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. Electronic address: cywang@ihm.ac.cn.
² Institute 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.
³ Department of Medicinal Chemistry, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
⁴ Department of Ophthalmology, The First Affiliated Hospital of USTC, State Key Laboratory of Eye Health, New Cornerstone Science Laboratory, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China. Electronic address: xuetian@ustc.edu.cn.
⁵ Department of Ophthalmology, The First Affiliated Hospital of USTC, State Key Laboratory of Eye Health, New Cornerstone Science Laboratory, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China. Electronic address: sym_ustc@ustc.edu.cn.
⁶ Department of Medicinal Chemistry, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China. Electronic address: chenhe@tmu.edu.cn.
⁷ Institute 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. Electronic address: caocan23@ustc.edu.cn.

PMID: 41232528
DOI: 10.1016/j.cell.2025.10.022

Abstract

Presynaptic 5-HT_1AR autoreceptors predominantly signal through G_i3 protein, mediating feedback inhibition that hampers the therapeutic efficacy of conventional antidepressants. By contrast, postsynaptic heteroreceptors mainly couple to G_o, which promotes antidepressant responses. However, selectively activating heteroreceptors while bypassing the negative feedback induced by autoreceptors remains a significant challenge. Here, we characterized the G_i/o subtype signaling profiles of 5-HT_1AR and determined its structures in complex with six agonists and three distinct G_i/o family proteins: G_oA, G_i3, and G_z. Combined with functional analysis, we elucidated the mechanisms underlying diverse agonist recognition modes and G_i/o subtype signaling selectivity of 5-HT_1AR. Furthermore, we designed a pathway-selective agonist, TMU4142, which exhibits high G_oA activity while minimizing G_i3 activation. Remarkably, TMU4142 demonstrated rapid antidepressant-like effects in a mouse model of depression. Collectively, these findings suggest that distinguishing heteroreceptors from autoreceptors based on their distinct downstream G_i/o signaling pathways could be a promising strategy to develop fast-acting antidepressants.

Keywords: 5-HT(1A)R; G(i/o) subtype selectivity; antidepressant; autoreceptors; drug discovery; feedback inhibition; heteroreceptors; ligand recognition; structural pharmacology.

MeSH terms

Animals
Antidepressive Agents* / chemistry
Antidepressive Agents* / pharmacology
Antidepressive Agents* / therapeutic use
Depression / drug therapy
Disease Models, Animal
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Piperidines
Pyrimidines
Receptor, Serotonin, 5-HT1A* / chemistry
Receptor, Serotonin, 5-HT1A* / metabolism
Serotonin 5-HT1 Receptor Agonists* / chemistry
Serotonin 5-HT1 Receptor Agonists* / pharmacology
Serotonin 5-HT1 Receptor Agonists* / therapeutic use
Signal Transduction / drug effects

Substances

Antidepressive Agents
Receptor, Serotonin, 5-HT1A
Serotonin 5-HT1 Receptor Agonists
3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
Piperidines
Pyrimidines