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A collaborative research team from the Universities of Oxford and Cambridge co-led by DPAG's Associate Professor Ana Domingos have developed a new weight-loss amphetamine that could potentially avoid the harmful side effects of traditional treatments.


Obesity is a major health issue across the world and is implicated in many serious health conditions such as diabetes, heart disease and cancer. Despite being officially declared a chronic disease, there are very few long-lasting and cost-effective treatments for obesity. Historically, amphetamine (AMPH) class drugs have been some of the most popular anti-obesity drugs to be prescribed and are widely considered to be the most effective while also being among the cheapest to produce. They work in the brain to reduce appetite and increase locomotion or stamina. However, these drugs are also known for strongly activating the sympathetic nervous system, the peripheral part of the nervous system known to accelerate the heart rate, constrict blood vessels and raise blood pressure. Consequently, as well as being addictive, they can present side effects such as dangerously increased heart rate and hypertension.  

A research team led by Associate Professor Ana Domingos and Dr Gonçalo Bernardes from the University Cambridge suspected that the cardiac side effects of amphetamines could originate in the brain. If this was the case, they hypothesised that if they could design a drug that did not pass the blood-brain barrier, they could avoid these unwanted outcomes, while perhaps retaining an anti-obesity action. In a new paper published in Cell Metabolism, the team have shown that the cardiac side effects of AMPH do indeed originate in the brain and have presented a modified amphetamine that does not enter the brain while avoiding its known side effects.

To prove their hypothesis, working with researchers in Portugal, the team attached polyethylene glycol (PEG) polymer chains to amphetamine, in a process known as PEGylation. PEGylation is often used to mask a drug from the body’s immune system, or to increase the hydrodynamic size (size in solution) of molecules. Through this process, they created a larger, PEGylated amphetamine, which they dubbed PEGyAMPH. Because of its larger size, PEGyAMPH cannot penetrate the blood-brain barrier and the team showed that it is indeed absent in the brains of mice treated with PEGyAMPH, which did not show suppressed feeding nor increased locomotion. The lack of behavioural effects presented further confirmation that the PEGyAMPH did not cross the blood-brain barrier.

The team then used different drug delivery routes to confirm that the cardiovascular effects of amphetamines are not caused peripherally but centrally instead, originating from the brain. Either compounds, if directly delivered onto the brain, induce cardiovascular side effects. Conversely, and unlike amphetamine, these noxious side effects are gone if the brain-sparing PEGyAMPH is delivered systemically.

They also found that the activation of peripheral sympathetic neurons, which receive signals from the brain, is required for centrally-acting amphetamines to be effective in stimulating lipolysis and promoting weight loss. It can be determined that the anti-obesity effect of an amphetamine treatment is not as effective in the absence of an intact sympathetic nervous system, despite its behavioural effects on appetite and locomotion.

PEGyAMPH can still favour the activation of sympathetic neurons and increase peripheral sympathetic output onto adipose tissues. The researchers have consequently coined the compound as sympathofacilitator, to distinguish it from its chemical predecessor, which is infamously coined as sympathomimetic. They showed that the effect of PEGyAMPH is mainly mediated by the β2-adrenoceptor (ADRB2), which they show to facilitate the activation of peripheral sympathetic neurons. These neurons were previously shown by Prof Domingos’ team to make fat to burn if they are triggered by descending signals from the brain. The researchers then demonstrated that PEGyAMPH protected mice against obesity despite the absence of behavioural effects, such as decreased appetite and increased locomotor activity. 

PEGyAMPH increased sympathetic-stimulated fat breakdown in the body, via a cellular process named lypolysis. It also increased thermogenesis, the process of heat production, which burns calories stored in fat. Importantly, although PEGyAMPH raises thermogenesis, unlike unmodified amphetamines, it does not cause higher core body temperature, because they have different actions on peripheral vasculature and therefore on thermoregulation. Amphetamine is a vasoconstrictor, whereas PEGyAMPH promotes vasodilation via smooth muscle relaxation, allowing for higher heat-dissipation which normalises core body temperature. Thus, the novel drug functions as an energy sink, whereby generation of heat is directly coupled to its dissipation. Prof Domingos said: “this is like turning on the heat and leaving the windows open during the winter: you’ll see your gas bill go up!”

The newly designed drug has several advantages over traditional amphetamine treatments for weight loss. Because it does not pass the blood-brain barrier, PEGyAMPH is not addictive and it also does not affect cardiovascular function, thus avoiding the negative side effects that amphetamines can cause. Moreover, it also improved blood glucose levels in mice by increasing sensitivity to insulin, thus preventing hyperinsulinemia, a condition that precedes the development of type 2 diabetes. Hence, PEGyAMPH reduces obesity with a size-effect comparable to that of AMPH, yet with a distinct mechanism in that it spares effects relating to brain action, overriding caloric intake by increasing energy expenditure.

While PEGyAMPH is currently only validated pre-clinically and is therefore still in the experimental stages, this new weight-loss drug brings hope for a safer and more cost-effective treatment than those currently available.  


The full paper ‘Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects’ can be read in Cell Metabolism.

Text credit: Instituto Gulbenkian de Ciência (IGC) for the press release.

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