Heart Attack Drug Bypasses Side-Effects

Scientists have improved the specificity of heart attack drugs such that they no longer cause heart stoppage.

AsianScientist (Mar. 24, 2014) – Scientists are a step closer to creating a new drug to reduce the damage caused by heart attacks without the serious side effects.

“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,” said author of the study, Professor Arthur Christopoulos from the Monash Institute of Pharmaceutical Sciences (MIPS).

Currently, drugs to minimize damage to the heart activate the adenosine A1 receptor, a G protein-coupled receptors (GPCR) found in the heart. However, activating the A1 receptor also has serious side effects.

“Correct dosage has been a serious challenge in clinical trials for A1 receptor drugs. 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,” said Professor Peter Scammells, co-author of the study.

Current GPCR drugs work either by fully activating or completely blocking receptors, treating the protein like a simple “on-off” switch. Scammells and Christopoulos’ research has 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”.

“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.

“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,” Christopoulos said.

The results, published in the Proceedings of the National Academy of Sciences (PNAS), will inform the next phase of the research that may someday result in a new drug for use by clinicians and emergency paramedics.

The article can be found at: Valant et al. (2014) Separation Of On-Target Efficacy From Adverse Effects Through Rational Design Of A Bitopic Adenosine Receptor Agonist.

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Source: Monash University; Photo: Dan Backman/Flickr/CC.

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