TMU4142
TMU4142 is a potent and selective serotonin 5-HT1A receptor biased agonist. 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.
Presynaptic serotonin 5-HT1A autoreceptors predominantly signal via the Gi3 pathway in the dorsal raphe nucleus 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. 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, and vilazodone, among others. On the other hand, the Gz pathway is thought to be involved in anxiolytic-like effects. 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.
TMU4142 produces rapid antidepressant-like effects in rodents without modifying serotonin levels or neuronal firing rates in the DRN. 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. 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.
TMU4142 was first described in the scientific literature by Chunyu Wang and colleagues in 2025. 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.