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

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.