Chemistry:TMU4142

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TMU4142 is a potent and selective serotonin 5-HT1A receptor biased agonist.[1] It is a preferential near-full agonist of the GoA pathway with weak agonism of the Gi3 pathway and little or no β-arrestin2 recruitment.[1]

Presynaptic serotonin 5-HT1A autoreceptors predominantly signal via the Gi3 pathway in the dorsal raphe nucleus (DRN) and are associated with feedback inhibition that may hamper therapeutic effects, whereas postsynaptic serotonin 5-HT1A heteroreceptors couple mainly to Go pathways in hippocampal and cortical areas and are thought to mediate antidepressant-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 as 8-OH-DPAT, buspirone, gepirone, F-15599 (NLX-101), and vilazodone, among others.[1] On the other hand, the Gz pathway is thought to be involved in anxiolytic-like effects.[1] Analogously to TMU4142, pindolol is a moderate-efficacy partial agonist of the Go pathways but a very weak partial agonist or antagonist of Gi pathways.[1]

TMU4142 produces rapid antidepressant-like effects in rodents without modifying serotonin levels or neuronal firing rates in the DRN.[1] This is in contrast to other serotonin 5-HT1A receptor agonists like buspirone and F-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 to serotonin reuptake inhibitors like fluoxetine, 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 the scientific literature by Chunyu Wang and colleagues in 2025.[1] It is a combined derivative or analogue of pindolol and azapirones like buspirone with improved pharmacological properties such as selectivity, biased agonism, and activational efficacy.[1]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 "Pathway-selective 5-HT1AR agonist as a rapid antidepressant strategy". Cell. November 2025. doi:10.1016/j.cell.2025.10.022. PMID 41232528. 



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