210302-17-3

BAM15 (210302-17-3) is a mitochondrial protonophore uncoupler with fewer off-target effects (EC50 = 270 nM in L6 myoblast mitochondria.)1,2 Compared to FCCP, an uncoupler of equal potency, BAM15 stimulates a higher maximum rate of mitochondrial respiration and does not depolarize the plasma membrane.2 Stimulates energy expenditure, protects against obesity and improves glycemic control in rodent models.3 Reverses diet-induced obesity and insulin resistance in mice.4 Attenuates transportation-induced apoptosis in iPS-differentiated retinal tissue.5

BAM 15, is a mitochondrial protonophore uncoupler that does not depolarize the plasma membrane and protects mice from acute renal ischemic-reperfusion injury.

BAM15 increases mitochondrial respiration rate and is also found to be less cytotoxic compared to other protonophore uncouplers such as carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Hindered oncogenic MAPK (mitogen-activated protein kinase ) signaling leads to BAM15 induced mitochondrial apoptotic pathway activation.

This novel mitochondrial uncoupler (FW = 340.29 g/mol), also named (2- fluorophenyl)-{6-[(2-fluorophenyl)amino]-(1,2,5-oxadiazolo[3,4-e]pyrazin- 5-yl)}amine, exhibits a broad effective range of H+ gradient-dissipating action without affecting plasma membrane electrophysiology. With FCCP as an equipotent positive control, BAM15 was found to be fully able to increase mitochondrial respiration in the presence of oligomycin over a broader concentration range than FCCP in both myoblasts and hepatocytes. BAM15 and FCCP had similar effects on mitochondrial depolarization in L6 myoblasts treated with concentrations of each uncoupler at 1 and 10 μM, as measured by tetramethylrhodamine (TMRM) fluorescence. Neither FCCP nor BAM15 donates electrons to the Electron Transport Chain. Although some non-protonophoric uncouplers increase proton transport into the matrix via interaction with the mitochondrial inner membrane adenine nucleotide translocase (ANT), neither BAM15 nor FCCP requires the ANT to increase mitochondrial respiration.

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1) Kenwood et al. (2015), Structure-activity relationships of furazano[3,4-b]pyrazines as mitochondrial uncouplers; Bioorg. Med. Chem. Lett., 25 4858 2) Kenwood et al. (2013), Identification of a Novel Mitochondrial Uncoupler That Does Not Depolarize the Plasma Membrane; Mol. Metab., 3 114 3) Axelrod et al. (2020), BAM15-mediated Mitochondrial Uncoupling Protects Against Obesity and Improves Glycemic Control; EMBO Mol. Med., Jun 10; e12088 4) Alexopoulos et al. (2020), Mitochondrial Uncoupler BAM15 Reverses Diet-Induced Obesity and Insulin Resistance in Mice; Nat. Commun., 11 2397 5) Tang et al. (2019), BAM15 Attenuates Transportation-Induced Apoptosis in iPS-differentiated Retinal Tissue; Stem Cell Res. Ther., 10 64