▶ Discovered a PAM regulator that binds well to the adenosine A1 receptor
▶ Researchers from the Australian rice plant era, thesis in the journal ‘Nature’
Chronic pain is one of the issues that place a great burden on the global health and medical community.
The number of patients with pain is increasing, but there is no proper treatment method, so the reality is that we rely heavily on opioid analgesics using opioids.
However, these narcotic analgesics have limited effectiveness and cause serious side effects such as respiratory function deterioration and drug addiction.
Neuropathic pain, a type of chronic pain, is also a disease in which opioid analgesics are frequently used.
Neuropathic pain can come from multiple sources, including bodily injury, viral infection, complications of multiple sclerosis or diabetes, and cancer treatment.
It is likely to open the way for the development of non-narcotic analgesics that safely and effectively treat such neuropathic pain.
A modulator that binds well to the adenosine A1 receptor, a potent therapeutic target for non-narcotic analgesics, has been discovered.
The results of this study, conducted by Arthur Christopoulos, a professor of pharmacy and pharmaceutical sciences in Australia, were published as a thesis in the journal ‘Nature’ on the 8th (local time).
The adenosine A1 receptor has long been recognized as a potent target of non-narcotic analgesics for neuropathic pain.
However, it has not been developed as an analgesic because it has not been able to find a molecule with accurate on-target selectivity and there is a high risk of side effects.
The research team of Monae era found that PAM (positive allosteric modulator) modulators that are positive for allosteric effects acted much more selectively on A1 receptors.
The allosteric effect refers to a change in the structure of the active site by binding of an activator to a specific site other than the active site that performs the original function of the protein.
By binding to other regions of the A1 receptor, PAM not only relieves neuropathic pain with minimal side effects, but also raises the level of action according to the strength of the spinal cord pain signal.
The research team also used cryoEM (cryoEM) to unravel the high-resolution structure of the A1 receptor, which binds both PAM and adenosine, which have analgesic effects.
This is the first time that the high-resolution atomic structure of the A1 receptor, which acts directly on non-narcotic analgesics, has been elucidated.
Wendy Imlach, Associate Professor, Head of the Pain Mechanism Lab at the Biomedical Discovery Institute (BDI), said, “This study has given us a deeper understanding of the mechanism of action of allosteric drugs.” .
Professor Christopoulos, the co-corresponding author of the paper, said, “As we are currently experiencing a global drug crisis, it is urgent to develop a safe and effective non-narcotic analgesic.” By leveraging that insight, we will be able to design non-narcotic allosteric drugs that effectively treat chronic pain.”