Novel drug candidates found for nerve pain and ischemic disease

Australian and Swedish scientists have discovered novel drug candidates which could ultimately lead to new effective treatments for conditions caused by tissue stress and inflammation, including neuropathic pain and ischemia-reperfusion injury. Their work has been published in the journal PNAS.

Neuropathic pain, also known as nerve pain, is often linked to inflammation in the peripheral and central nervous systems. Ischemia-reperfusion injury is tissue damage that occurs when blood flow is restored to an area that has been deprived of oxygen, ie, following a heart attack.

The study, led by the Monash Institute of Pharmaceutical Sciences (MIPS) in collaboration with Uppsala University, focused on the discovery of drug-like candidates to target the adenosine A1 receptor (A1R) subtype. A1Rs are widely distributed in the brain and heart and play a key role in communication between neurons.

Health conditions triggered by tissue stress benefit from A1R activation, and thus this receptor has been identified as a promising target for ischemia-reperfusion injury and chronic neuropathic pain. However, the successful development of drugs targeting A1R has remained challenging due to unwanted effects: both on-target, such as slowing heart rate, and off-target, caused by interactions with other adenosine receptor subtypes.

The research team used a combination of advanced technologies to discover a novel set of subtype-selective A1R positive allosteric modulators (PAMs) — drug candidates that specifically target A1R and enhance its activity without affecting other adenosine receptors. Unlike traditional agonists that fully activate A1R and often cause side effects like slowed heart rate, these PAMs act like a ‘dimmer switch’ rather than an on/off switch — subtly enhancing the receptor’s response only when and where it is naturally active, offering more precise control with fewer on-target effects.

The team’s discovery paves the way for potential new treatments for neuropathic pain, ischemia-reperfusion injury and other diseases linked to tissue stress and inflammation, without accompanying side effects. Their work thus marks a pivotal advance in A1R-targeted drug development, according to co-first author Dr Anh Nguyen from MIPS.

“When the new drug candidates we’ve discovered bind to A1R they are able to modulate neuron activity in such a way that unwanted side effects, such as cardiac reactions, are no longer a hindrance,” Nguyen said. “This has been a significant hurdle in the development of drugs targeting A1R, so we are very excited by this discovery and its potential to enable safer, more effective treatments for a range of conditions.”

A1R is part of the G-protein-coupled receptor (GPCR) family — the largest drug target class behind many major life-changing medical advancements in recent decades. Drugs that target the GPCR family make up about 34% of all US FDA-approved drugs, including Cobenfy (for schizophrenia) and semaglutide (Ozempic, Wegovy) for diabetes and obesity.

Co-lead author Dr Lauren May, also from MIPS, said the team’s discovery can largely be attributed to significant developments in drug screening technologies and computational techniques.

“A much deeper pharmacological understanding of GPCRs, combined with technological advancements, has collectively transformed the potential of this incredible family of drug targets which, in recent years, has led to new classes of life-changing drugs for millions of people around the world,” May said.

“In particular, the study showcases the efficacy of using cryo-electron microscopy (cryo-EM) — a technology which enabled the team to identify and study the architecture of A1R allosteric site to target it at a molecular level. We then applied an algorithm to screen over 160 million compounds and narrowed the list to 26 top-ranked candidates for experimental testing, which ultimately led us to discover the new set of A1R selective PAMs.”

Co-first author Dr Nicolas Panel, from Uppsala University, said the success of the study was driven by developing a new approach to virtually screen drug candidates for challenging allosteric pockets.

“Unlike traditional drug-binding sites, the A1R’s allosteric site is shallow and faces the membrane, making it very difficult to target,” Panel said. “To overcome this, we used molecular dynamics simulations to model how the membrane environment affects pocket shape, then screened a large compound library against this structure. This allowed us to identify new chemical scaffolds that would have been missed by standard methods.”

Uppsala’s Professor Jens Carlsson, who co-led the computational strategy, added, “This work shows how structure-based drug discovery can now be extended to membrane-facing pockets that were previously considered undruggable.”

The next phase of the research will focus on further preclinical development of the lead compounds and testing of their efficacy in disease models of neuropathic pain and ischemia-reperfusion injury. The team hopes these findings will lay the groundwork for future clinical trials and the development of safer, more targeted therapeutics for conditions involving A1R signalling.

Image caption: Cryo-EM structure of the human adenosine A1 receptor (A1R, white) in complex with the orthosteric agonist adenosine (magenta) and the allosteric modulator MIPS521 (cyan). Image generated by Dr Anh Nguyen, Monash University.