Amphetamines are efficacious therapeutic compounds approved for the treatment of obesity. This class of therapeutics, however, are associated with a number of adverse cardiovascular effects, which are thought to be caused by the drugs acting peripherally. Now, Ana Domingos and colleagues show that it is the actions of amphetamines in the brain that cause these adverse effects.
The amphetamine class of anti-obesity drugs, which includes the FDA-approved phentermine, work by supressing appetite and increasing locomotion. In the present study, Domingos and colleagues show that the cardiovascular adverse effects, which include tachycardia and increased blood pressure, can be arrested through the addition of polyethylene glycol (PEG) polymer chains to amphetamine.
“Following our paper in Nature Medicine in 2017 where we showed that some macrophages express the transporter for noradrenaline and that the loss of function of this transporter in these macrophages outside the brain protects against obesity, we set out to see if we could generate these anti-obesity effects pharmacologically,” explains Domingos. The team, in collaboration with Gonçalo Bernardes, went on to develop a method for the ablation of sympathetic neurons in mice. “In that study we demonstrated that, compared with littermates that have an intact sympathetic nervous system, regionally sympathectomized mice were extremely susceptible to obesity, despite showing no differences in feeding behaviour or in locomotor activity,” adds Domingos. It is the premise of that study that is the basis of the present study.
The team started by using different drug delivery approaches to define the origin of the cardiovascular adverse effects of amphetamines. By combining intracerebroventricular versus intraperitoneal delivery with different modes of assessing cardiac and vascular effects of amphetamine, the team were able to map the adverse effects to the brain. “Dissecting the origin of the cardiovascular adverse effects of amphetamine is extremely relevant,” explains Domingos. “It was always thought that the noxious effects of amphetamines on the cardiovascular system resulted from their direct stimulation of the cardiac sympathetic nerves themselves, rather than from central action in the brain.”
Next, the investigators developed a brain-sparing drug that could facilitate the activity of sympathetic neurons without affecting behaviour. “Given that amphetamine is not only a sympathomimetic drug, but also a potent anorexigenic agent, we attached PEG polymer chains to it to prevent it from entering the brain,” adds Inês Mahú, lead author on the study. The addition of PEG polymer chains (a chemical reaction known as pegylation) is used to increase the hydrodynamic size of a molecule. In the case of PEG–amphetamine, its large size prevents it from crossing the blood–brain barrier, something that the authors confirmed using mass spectrometry techniques and also by performing behavioural tests.
Finally, Domingos and colleagues used multiple techniques, including genetic sympathectomy and pharmacology, to investigate the mechanisms behind the anti-obesity effects of PEG–amphetamine. “We found that the effect of PEG–amphetamine is mainly mediated by the β2 adrenoceptor,” adds Mahú. “The activation of the β2 adrenoceptor promotes vasodilation and increases heat dissipation, which normalizes core body temperature in the presence of increased thermogenesis.”
“This proof-of-principle study highlights an untapped physiological mechanism that promotes weight loss, independently of behaviour”
This proof-of-principle study highlights an untapped physiological mechanism that promotes weight loss, independently of behaviour. “Although PEG–amphetamine was developed as a proof of concept,” concludes Domingos, “this new weight loss drug might inspire the development of other compounds and bring hope for a safer and more cost-effective treatments than those currently available.”
Mahú, I. et al. Brain-sparing sympathofacilitators mitigate obesity without adverse cardiovascular effects. Cell Metab. https://doi.org/10.1016/j.cmet.2020.04.013 (2020)
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Morris, A. Unravelling novel weight loss mechanisms. Nat Rev Endocrinol 16, 343 (2020). https://doi.org/10.1038/s41574-020-0374-4