'Dimmer switch' drug candidates offer hope for safer nerve pain and ischemic disease treatments

Scientists have recently identified new drug-like candidates that hold promise for developing safer and more effective treatments for conditions arising from tissue stress and inflammation. These include neuropathic pain, commonly known as nerve pain, and ischemia-reperfusion injury, a type of tissue damage that occurs when blood flow is restored after being deprived of oxygen, such as following a heart attack.

The breakthrough study, conducted by the Monash Institute of Pharmaceutical Sciences (MIPS) in collaboration with Uppsala University in Sweden and published in the Proceedings of the National Academy of Sciences (PNAS), focused on targeting the adenosine A1 receptor (A1R). This receptor is widely distributed in the brain and heart and plays a crucial role in neuron communication. Activation of A1R has been linked to benefits in conditions caused by tissue stress, making it an attractive target for therapies addressing ischemia-reperfusion injury and chronic neuropathic pain.

Developing drugs that precisely target A1R has been challenging due to undesirable side effects, such as slowing heart rate, and the potential to interact with other adenosine receptor subtypes. To overcome these hurdles, researchers employed advanced technologies to discover a new set of subtype-selective positive allosteric modulators (PAMs)—drugs that specifically enhance A1R activity without affecting other related receptors.

Unlike traditional drugs that fully activate the receptor and can cause side effects, these PAMs act like a "dimmer switch," subtly boosting the receptor's natural response only when needed. This approach allows for more precise control of neuronal activity, potentially leading to therapies that effectively treat pain and tissue injury while minimizing side effects.

The discovery was facilitated by state-of-the-art techniques, including cryo-electron microscopy (cryo-EM), which enabled detailed visualization of the receptor's architecture at a molecular level. By combining computational algorithms that screened over 160 million compounds, the team identified 26 top candidates for experimental testing, ultimately leading to the discovery of these novel PAMs.

Dr. Anh Nguyen, the lead researcher from MIPS, highlighted the significance of the findings, stating that these drug candidates could revolutionize A1R-targeted therapies by avoiding adverse cardiac reactions that have hampered previous drug development efforts. The team’s innovative approach also utilized molecular dynamics simulations to understand how the receptor’s membrane environment influences targeting strategies, enabling them to identify chemical scaffolds that were previously considered undruggable.

Looking ahead, the research team plans to advance these compounds through preclinical testing and examine their efficacy in models of neuropathic pain and ischemia-reperfusion injury. The overarching goal is to pave the way for clinical trials and develop safer, targeted medications for stress-related conditions involving A1R signaling.

This research underscores the expanding potential of GPCR (G-protein-coupled receptor) drugs, which constitute approximately 34% of all FDA-approved medications, including treatments for schizophrenia and diabetes. The progress achieved through structure-based drug discovery and advanced computational techniques demonstrates how modern science continues to unlock new possibilities for treating complex diseases.