Additional Research Compound · For laboratory research use only
BAM15 (N5,N6-bis(2-fluorophenyl)-1,2,5oxadiazolo[3,4-b]pyrazine-5,6-diamine) is a small-molecule mitochondrial protonophore uncoupler. It was identified in 2014 from a chemical library screen for uncouplers that, unlike FCCP and 2,4-dinitrophenol, do not depolarise the plasma membrane1. The structure-activity relationships of the furazanopyrazine scaffold were reported the following year2.
Published research covers cell respirometry, isolated mitochondria and model membranes, vascular smooth muscle, and mouse models of renal ischaemia-reperfusion injury, diet-induced obesity and sepsis1,3,4,5,6,7.
As described in the research literature
As described in the research literature, mitochondrial uncouplers are lipophilic weak acids that carry protons into the mitochondrial matrix independently of ATP synthase, uncoupling nutrient oxidation from ATP production1. Compared with FCCP at equal potency, BAM15 was reported to stimulate a higher maximal rate of mitochondrial respiration in cultured cells and to be less cytotoxic1. Structure-activity work identified the furazan, pyrazine and aniline rings and the compound's pKa as important for its protonophore activity2.
Biophysical studies confirmed BAM15 as an anionic protonophore in planar bilayers and liposomes with a potency close to CCCP. In isolated rat liver mitochondria its uncoupling action was partly reversed by carboxyatractyloside, implicating the adenine nucleotide translocase, and in molluscan neurons it did cause plasma membrane depolarisation, although more slowly than CCCP3. In vascular smooth muscle cells, BAM15 activated AMPK more potently than CCCP, niclosamide, metformin or AICAR4.
What published studies have examined
Cell respirometry and plasma membrane potential measurements compared BAM15 with FCCP1, and analogues of the scaffold were profiled for protonophore activity2. Planar bilayers, liposomes, isolated rat liver mitochondria, Bacillus subtilis and molluscan neurons were used to characterise its protonophoric action3.
Mouse studies examined bioavailability, nutrient oxidation, body fat mass, food intake, lean mass, body temperature and markers of toxicity, with hyperinsulinaemic-euglycaemic clamps used to assess insulin sensitivity5. A separate study in C57BL/6J mice and cultured cells examined respiratory kinetics, insulin action, nutrient uptake and AMPK activation6.
The identification study examined BAM15 in a mouse model of acute renal ischaemia-reperfusion injury1. A cecal ligation and puncture sepsis model in mice examined mortality, kidney damage, mitochondrial DNA release and the role of neutrophils7.
Rat mesenteric arteries and A10 vascular smooth muscle cells were used to compare BAM15 with CCCP and niclosamide on vasorelaxation, cytotoxicity, mitochondrial membrane potential, fission, reactive oxygen species and AMPK activation4.
Sources [4]
Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane.
Kenwood BM, Weaver JL, Bajwa A, et al. Molecular Metabolism, 2014.
Structure-activity relationships of furazano[3,4-b]pyrazines as mitochondrial uncouplers.
Kenwood BM, Calderone JA, Taddeo EP, et al. Bioorganic & Medicinal Chemistry Letters, 2015.
Protonophoric action of BAM15 on planar bilayers, liposomes, mitochondria, bacteria and neurons.
Firsov AM, Popova LB, Khailova LS, et al. Bioelectrochemistry, 2021.
Mitochondrial uncoupler BAM15 inhibits artery constriction and potently activates AMPK in vascular smooth muscle cells.
Tai Y, Li L, Peng X, et al. Acta Pharmaceutica Sinica B, 2018.
Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice.
Alexopoulos SJ, Chen SY, Brandon AE, et al. Nature Communications, 2020.
BAM15-mediated mitochondrial uncoupling protects against obesity and improves glycemic control.
Axelrod CL, King WT, Davuluri G, et al. EMBO Molecular Medicine, 2020.
BAM15 treats mouse sepsis and kidney injury, linking mortality, mitochondrial DNA, tubule damage, and neutrophils.
Tsuji N, Tsuji T, Yamashita T, et al. The Journal of Clinical Investigation, 2023.
This page is provided for research and educational reference only. It does not constitute medical advice, dosing guidance, or a recommendation for use. All compounds are strictly for laboratory and in-vitro research purposes.