BAM15, the 'light' version of DNP
Australian researchers at the University of New South Wales are testing a new pharmacological weight loss drug that works in much the same way as DNP - but without all of those terrible side effects. We read their publication in Nature Communications with growing interest.
As long as the obesity epidemic continues to swell, the search for pharmacological weight loss drugs continues. Part of that quest takes place with the dangerous but effective weight loss drug DNP in mind. Would it be possible to design a molecule that is as effective as DNP, but not as extremely dangerous?
DNP is a mitochondrial uncoupler: it ensures that the cell's power plants can still convert nutrients into energy, but cannot properly store them in energy molecules such as ATP.
American researchers at Yale University are studying a methylated analog of DNP, DNPME. [Cell Metab. 2013 Nov 5;18(5):740-8.] Japan's Otsuka Pharmaceutical is conducting trials with OPC-163493. [Nat Commun. 2019 May 15;10(1):2172.] And the Australians who produced the research covered by this report are experimenting with N5, N6-bis (2-fluorophenyl) [1,2,5] oxadiazolo [3,4-b ] pyrazine-5,6-diamine in short: BAM15.
The Australians gave mice oral doses of BAM15 and saw that in the hours after administration, the animals' oxygen consumption - and thus their calorie consumption - increased by several tens of percent. The effect was temporary. That's because the half-life of BAM15 in mice is a mere 1.7 hours.
In other experiments, in which mice were fed BAM15 mixed with their food, the researchers found that BAM15 only increased calorie expenditure at night. That is not surprising, because mice are nocturnal animals, and therefore prefer to eat when it is dark. BAM15 did not increase the amount of physical activity.
If the mice had been human adults, they would have received about one gram of BAM15 daily.
In yet another experiment, the researchers fed mice with extra sugar and fat [WD], making the animals fatter. If the mice also received BAM15, their fat mass grew less, not at all, or even decreased. The human equivalent of the doses at which these effects occurred were half, one, and one and a half grams of BAM15 per day, respectively.
BAM15 did not increase the mice's body temperature, decrease lean body mass, or increase free radical activity. As far as the researchers could find out, BAM15 also increases insulin sensitivity.
"BAM15 represents a rare mitochondrial uncoupler that prevents and reverses obesity without affecting food intake or lean mass", the researchers write.
"One limitation of BAM15 is low aqueous solubility, but this property did not affect oral bioavailability and indeed low aqueous solubility is an important parameter that enables BAM15 to penetrate membranes and enter mitochondria."
"Another limitation of BAM15 is a 1.7 h half-life and future directions will investigate formulation strategies to improve exposure."
"Collectively, the data presented herein supports further development of BAM15 as a potential therapeutic for obesity and metabolic diseases."
A pharmacological slimming aid with an effective dose of one gram per day? We are a little less optimistic than the Australians...
Nat Commun. 2020 May 14;11(1):2397.
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