TMU4142

TMU4142 is a selective 5-HT1a agonist with high GoA activity. Its Gi3 activity is relatively weak, allowing it to swiftly produce antidepressant-like effects or inhibit serotonergic neuron firing without significantly activating 5-HT1a autoreceptors in the DRN region. In mouse models of depression, TMU4142 demonstrates rapid-onset antidepressant effects. TMU4142 is applicable for antidepressant research.

TMU4142 activates the GoA signaling pathway and shows weaker activity on the Gi3 pathway. It does not display detectable activity on the β-arrestin-2 pathway related to the 5-HT 1a receptor. The compound demonstrates higher potency at the 5-HT 1a receptor, while reducing activity on the β-adrenergic receptors.

TMU4142, administered intraperitoneally at doses of 0.3 or 1.5 mg/kg, displays a preference for GoA signaling with minimal activity on Gi3. It selectively activates the GoA signaling pathway, which is primarily postsynaptic and associated with antidepressant effects. This selectivity avoids Gi3-mediated presynaptic autoreceptor feedback inhibition, thereby maintaining the synthesis and release of 5-HT in the DRN region in a depression model induced by chronic restraint stress in C57BL/6 mice.