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Scientists Discover Potential Heart Attack Treatment Without Side Effects

Protein receptors have ‘dimmer switch’

Scientists in Australia are a step closer to creating a new drug to stop a heart attack in its tracks and reduce the damage caused, without causing any adverse effects.

The new findings, from Monash University, were published March 11 in the Proceedings of the National Academy of Sciences USA.

Researchers combined molecular pharmacology and medicinal chemistry to achieve new insights into a specific protein belonging to the family of G protein-coupled receptors (GPCRs). After successfully combining two molecules, they are a step closer to creating a new class of drug that is more targeted and that could cause minimal side effects.

GPCRs play a role in most diseases, including cardiovascular disease, obesity, diabetes, neuropsychiatric disorders, inflammation, and cancer. Almost half of all current medications use GPCRs to achieve their therapeutic effects.

Current GPCR drugs work by fully activating or completely blocking receptors, treating the protein like a simple “on-off” switch. The researchers have discovered alternative recognition sites on GPCRs that can be targeted by drugs to fine-tune the behavior of the protein, basically converting the “on-off” switch into a “dimmer switch.” Lead investigator Professor Arthur Christopoulos said it was this insight that enabled the new breakthrough.

“When a heart attack strikes, heart cells die because of a lack of oxygen and nutrients. But even more damage is caused when the blood rushes back to the heart cells due to the release of inflammatory chemicals and damaging free radicals,” Christopoulos said.

Currently, drugs used to minimize damage to the heart activate the adenosine A1 receptor, a GPCR found in the heart. However, activating the A1 receptor also slows down the heart, and too much activation can stop the heart.

“Correct dosage has been a serious challenge in clinical trials for A1 receptor drugs,” said co-investigator Professor Peter Scammells. “The consequences are serious; a dosage that is too high can stop the heart from beating. Too low, and the drug fails to prevent cell damage. Getting this balance right has been a big problem.”

Christopoulos said the new study focused on finding ways to activate GPCR proteins in order to achieve the beneficial effects (protection) without the side effects (slowing the heart).

“We turned to our knowledge of alternative recognition sites on the A1 receptor and specifically designed a new class of molecule that contained two active components linked together — one binding to the main site on the receptor for activation, and another binding to the alternative site for fine-tuning of the activity,” Christopoulos explained. “Our ‘dimmer switch’ strategy worked, resulting in a molecule that protected heart cells but did not affect heart rate at all — at least in our animal models.”

“The beauty of this protein is that if you activate it effectively, you minimize the heart attack and protect the heart cells, and that’s something that’s never been done before.”

The new findings will inform the next phase of the research to develop a new drug that could potentially be made available for use by clinicians and emergency paramedics.

Source: Monash University; March 11, 2014.

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