Discovery of a Novel, Potent, and Selective 5‑Hydroxytryptamine 2B Receptor Antagonist that Induces Mitochondrial...

Serotonin, or 5-hydroxytryptamine (5-HT), is a multifaceted neurotransmitter that plays a vital role in the central nervous system (CNS). Beyond the CNS, 5-HT is intricately involved in modulating hemostasis, immune response, blood pressure, and metabolism in tissues such as skeletal muscle, heart, and kidney. Accumulating evidence highlights the interplay between 5-HT receptors and mitochondrial bioenergetics. Here, we report the discovery of a novel, potent, and selective 5-hydroxytryptamine 2B receptor (5-HT_2BR) antagonist, MARY1, which induces mitochondrial biogenesis (MB) in the kidney. MARY1 is a small molecule belonging to the pyridinylpiperazine class that exhibits selectivity and moderate affinity (K _i = 764 nM) for the human 5-HT_2BR, as well as efficacy (IC₅₀ = 380 nM; E _max = 90%) in cellular-based binding and functional assays. Treatment with MARY1 (1 nM) increases mitochondrial respiratory capacity, mitochondrial protein levels, and mitochondrial number in renal proximal tubule cells (RPTCs). Mechanistically, the MB effects of MARY1 in RPTCs are mediated through 5-HT_2BR and the activation of dual cell signaling pathways: PI3K/AKT and RAS/MEK/ERK. Moreover, MARY1 administration in mice and rats induces renal cortical MB, and increases levels of mitochondrial and fatty acid oxidation proteins. These findings identify MARY1 as a selective and potent 5-HT_2BR antagonist that induces MB and enhances mitochondrial function in the kidney, offering a potential therapeutic strategy for metabolic and mitochondrial dysfunction-associated renal disorders.