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-HT2BR) 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 (Ki = 764 nM) for the human 5-HT2BR, as well as efficacy
(IC50 = 380 nM; Emax = 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-HT2BR 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-HT2BR antagonist that induces MB and enhances
mitochondrial function in the kidney, offering a potential therapeutic
strategy for metabolic and mitochondrial dysfunction-associated renal
disorders.