Discovery of a Novel, Potent, and Selective 5-Hydroxytryptamine 2B Receptor Antagonist that Induces Mitochondrial Biogenesis in the Kidney

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, <b>MARY1,</b> which induces mitochondrial biogenesis (MB) in the kidney. <b>MARY1</b> is a small molecule belonging to the pyridinylpiperazine class that exhibits selectivity and moderate affinity (<i>K</i> _i = 764 nM) for the human 5-HT_2BR, as well as efficacy (IC₅₀ = 380 nM; <i>E</i> _max = 90%) in cellular-based binding and functional assays. Treatment with <b>MARY1</b> (1 nM) increases mitochondrial respiratory capacity, mitochondrial protein levels, and mitochondrial number in renal proximal tubule cells (RPTCs). Mechanistically, the MB effects of <b>MARY1</b> in RPTCs are mediated through 5-HT_2BR and the activation of dual cell signaling pathways: PI3K/AKT and RAS/MEK/ERK. Moreover, <b>MARY1</b> administration in mice and rats induces renal cortical MB, and increases levels of mitochondrial and fatty acid oxidation proteins. These findings identify <b>MARY1</b> 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.