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The researchers thus coined the compound as sympathofacilitator,to distinguish it from its chemical predecessor, the sympathomimetic class. "And it does this in a different way of the unmodified amphetamine, namely by not entering the brain and by not binding to some of the well-known molecular targets of amphetamine", adds Gonçalo Bernardes. PEGyAMPH can still favor the activation of sympathetic neurons and increase peripheral sympathetic output onto adipose tissues. Cellular changes in astrocytes play a crucial role in regulating outcomes for CNS disorders.Major study reveals key differences in brain structure between people with and without anorexia.Targeting thalamic circuits could reverse Parkinson’s symptoms in mice."This means 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", explains Inês Mahú. 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. Conversely, and unlike amphetamine, these noxious side effects are gone if the brain-sparing PEGyAMPH is delivered systemically. Either compounds, if directly delivered onto the brain, induce cardiovascular side effects. 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. This lack of behavioral effects was another confirmation that the PEGyAMPH did not indeed cross the blood-brain barrier. Because of its larger size, PEGyAMPH cannot penetrate the blood-brain barrier and the team showed that it is indeed absent is the brains of mice treated with PEGyAMPH, which did not show suppressed feeding nor increased locomotion. Through this process, they created a larger, PEGylated amphetamine, which they dubbed PEGyAMPH. "PEGylation is often used to mask a drug from the body's immune system, or to increase the hydrodynamic size of molecules to alter their distribution in the body", explains Gonçalo Bernardes. To test their hypothesis, they attached polyethylene glycol (PEG) polymer chains to amphetamine, in a process known as PEGylation. And if this was true, they imagined 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. However, the researchers suspected that the cardiac side effects of amphetamines could indeed originate in the brain. It was always thought that amphetamine's noxious effects on the cardiovascular system resulted from a their direct stimulation of the cardiac sympathetic nerves themselves, rather than from an central action in the brain, where we know it acts, for instance, to supress appetite, despite the lack of experimental evidence favoring one mechanism over the other".Īna Domingos, principal investigator at the Instituto Gulbenkian de Ciência (IGC) and Associate Professor of the University of Oxford 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.Īmphetamines are thus infamously coined as sympathomimetic. Amphetamines are one of the few and they reportedly act in the brain to reduce appetite and increase locomotion or stamina. Now, the team of Ana Domingos, principal investigator at the Instituto Gulbenkian de Ciência (IGC) and Associate Professor of the University of Oxford, together with Gonçalo Bernardes, principal investigator at the Instituto de Medicina Molecular (IMM) and Reader at the University Cambridge, have modified amphetamine so that does not enter the brain while avoiding its known side effects.ĭespite being officially declared a chronic disease there are very few long-lasting and cost-effective treatments for obesity. They work in the brain by suppressing appetite but, besides being addictive, can also have dangerous side effects such as increased heart rate, hypertension and hyperthermia. Historically, amphetamine-like drugs such as FDA-approved phentermine have been some of the most popular anti-obesity drugs that have ever been prescribed.
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Researchers developed a new weight loss amphetamine that could potentially avoid the side effects of older treatments.