Class of Molecules May Offer Opioid Alternative for Treating Pain
A class of molecules called positive allosteric modulators, or PAMs, may be useful in treating pain caused by nerve damage — a common symptom of multiple sclerosis (MS) — according to a new study that sheds light on how these molecules work.
The international team of researchers behind the study say their findings highlight the potential of these PAMs to serve as a non-opioid alternative for the management of chronic pain.
“The world is in the grip of a global opioid crisis and there is an urgent need for non-opioid drugs that are both safe and effective,” Arthur Christopoulos, a professor at Monash University, in Australia, and co-author of the study, said in a press release.
The study, “Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia,” was published in Nature.
Protein receptors play key roles in governing the behavior of cells in the body. Generally, these receptors sit on the surface of a cell, inactive, until they come in contact with the specific molecule — termed the “ligand” — for which they are a receptor. Once the receptor binds its ligand, it becomes activated and sends signals into the cell that affect the cell’s behavior.
A particularly common kind of protein receptor is the G protein-coupled receptor or GPCR. When this type of receptor binds to its ligand, it, as its name suggests, sends signals into the cell using an associated protein called a G protein.
In the context of pain, a specific GPCR called the A1 receptor, or A1R, has gained particular interest from researchers. That’s because it is well-established that activating A1R is antinociceptive, which means that “turning on” the receptor blocks the activity of the nerve cells responsible for sensing pain.
The most common strategy for activating a protein receptor such as A1R is to use an agonist — effectively, a molecule that mimics the receptor’s natural ligand, which in this case is called adenosine. However, A1R agonists have had limited utility because they often also activate other protein receptors, causing unwanted “off-target” effects.
When a ligand binds to a receptor, the ligand attaches to a specific part of the receptor called the binding site. As they mimic ligands, agonists also attach to the binding site.
By contrast, positive allosteric modulators increase the activity of a receptor by binding to a place other than the binding site, called the allosteric site.
“The A1R was the first GPCR for which synthetic, small-molecule positive allosteric modulators (PAMs) were described,” the researchers wrote.
But, they added, “despite years of research, the location of allosteric sites on the A1R remains — to our knowledge — unknown.”
The researchers first tested the analgesic or pain-lessening properties of several PAMs in a rat model of pain caused by nerve damage (neurotropic pain). The team, led by scientists from Monash Institute of Pharmaceutical Sciences and the Monash Biomedicine Discovery Institute (BDI), showed that these PAMs could reduce pain, and that a PAM called MIPS521 was especially effective.
A battery of tests — including imaging the molecules with electron microscopes and running computer simulations — were then conducted to understand how MIPS521 affected the A1R. These studies uncovered the specific location where the PAM attached to A1R.
The results also showed that, when MIPS521 was bound to the receptor, the receptor was bound more tightly to its G protein, used to send signals into the cell when the receptor is activated. In essence, this suggests that the PAM makes it easier for A1R to activate when it binds to its ligand.
According to the researchers, the study has led to a better understanding of the mechanisms underpinning allosteric drug actions.
“One of the exciting things we found is that not only were the PAMs able to decrease neuropathic pain with minimal unwanted effects, but they actually increase their level of effectiveness as the pain signals in the spinal cord get stronger — thus highlighting the potential for allosteric medicines that are uniquely sensitive to disease context,” said Wendy Imlach, PhD, head of the pain mechanisms lab at BDI and a study co-author.
Given what the scientists call a current “over-reliance on opioid painkillers, which provide limited relief in patients with chronic (particularly neuropathic) pain,” the results of this study highlight other potential therapeutic targets for managing pain.
“Our findings have broad implications for understanding the molecular basis of GPCR allosteric modulation and can facilitate rational, structure-based drug design of improved PAMs at an important therapeutic target,” the researchers concluded.
The team said their work could lead to the development of non-opioid painkillers.
“This multidisciplinary study now provides a valuable launchpad for the next stage in our drug discovery pipeline, which will leverage structure-based insights for the design of novel non-opioid allosteric drugs to successfully treat chronic pain,” Christopoulos said.
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