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TMU4142

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Pharmaceutical compound
TMU4142
Clinical data
Other namesTMU-4142
Drug classSerotonin5-HT1A receptorbiased agonist
ATC code
  • None
Chemical and physical data
FormulaC23H30N3O4
Molar mass412.510 g·mol−1
3D model (JSmol)
  • O[C](CNCCCN1C(=O)CC2(CCCC2)CC1=O)COc3cccc4[nH]ccc34
  • InChI=1S/C23H30N3O4/c27-17(16-30-20-6-3-5-19-18(20)7-11-25-19)15-24-10-4-12-26-21(28)13-23(14-22(26)29)8-1-2-9-23/h3,5-7,11,24-25,27H,1-2,4,8-10,12-16H2
  • Key:NJZRIWWCDITGNS-UHFFFAOYSA-N

TMU4142 is apotent andselectiveserotonin5-HT1A receptorbiased agonist.[1] It is a preferential near-full agonist of the GoA pathway with weak agonism of the Gi3 pathway and little or noβ-arrestin2 recruitment.[1]

Presynaptic serotonin 5-HT1Aautoreceptors predominantly signal via the Gi3 pathway in thedorsal raphe nucleus (DRN) and are associated with feedback inhibition that may hamper therapeutic effects, whereaspostsynaptic serotonin 5-HT1Aheteroreceptors couple mainly to Go pathways inhippocampal andcortical areas and are thought to mediateantidepressant-like effects.[1] As such, TMU4142 is a selective postsynaptic serotonin 5-HT1A receptor agonist with the potential for greater antidepressant activity than other serotonin 5-HT1A receptor agonists, such as8-OH-DPAT,buspirone,gepirone,F-15599 (NLX-101), andvilazodone, among others.[1] On the other hand, the Gz pathway is thought to be involved inanxiolytic-like effects.[1] Analogously to TMU4142,pindolol is a moderate-efficacypartial agonist of the Go pathways but a very weak partial agonist orantagonist of Gi pathways.[1]

TMU4142 produces rapid antidepressant-like effects in rodents without modifyingserotonin levels orneuronalfiring rates in the DRN.[1] This is in contrast to other serotonin 5-HT1A receptor agonists like buspirone andF-13714, which are strong presynaptic serotonin 5-HT1A receptor agonists and reduce DRN serotonin levels and neuronal firing rates.[1] It is also in contrast toserotonin reuptake inhibitors likefluoxetine, which work by elevating serotonin levels, in turn activating both pre- and post-synaptic serotonin 5-HT1A receptors, and which did not show rapid antidepressant-like effects in rodents.[1]

TMU4142 was first described in thescientific literature by Chunyu Wang and colleagues in 2025.[1] It is a combinedderivative oranalogue ofpindolol andazapirones like buspirone with improved pharmacological properties such as selectivity, biased agonism, and activational efficacy.[1]

See also

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References

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  1. ^abcdefghijkWang C, Zhang N, Shao Y, Li T, Zhang M, Gao M, et al. (November 2025). "Pathway-selective 5-HT1AR agonist as a rapid antidepressant strategy".Cell.doi:10.1016/j.cell.2025.10.022.PMID 41232528.
5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT2
5-HT2A
5-HT2B
5-HT2C
5-HT3–7
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7
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