Designing Pain-Relieving Drugs That Avoid Opioid Addiction

Developing a new wave of pain-relieving drugs without side effects has attained a first step by researchers at the University of Maryland School of Medicine and Washington University. In this first step, researchers have mapped the 3D structure of the specific molecules acting on these drugs. Opioids remain the most potent and effective pain relievers in medicine, but they are also the most addictive drugs that can halt a person's ability to breathe during an overdose which can be deadly. Researchers have been racing to develop safer pain reliever drugs that target a specific molecule found in the brain and not elsewhere in the body, like present in other drugs (1^✔ ✔Trusted Source
New Technologies for Elucidating Opioid Receptor Function

Go to source).

Previous research suggests that such drugs may not lead to addiction or death due to overdose, but the currently known drugs that target these kappa opioid receptors have their own set of unacceptable side effects, including depression and psychosis.

Structure of Opioid Receptors May Reveal How to Design Better Pain Relievers

In this new study published in the journal Nature, researchers discovered what instructs the molecules acting on pain-relieving drugs to change their shape, which uniquely binds to drugs in a lock and key pattern.

Aside from relieving pain, opioid receptors are also involved in everything from sensing taste and smell to digestion and breathing, as well as responding to many of the body hormones. The way these molecules can influence so many functions around the body is by acting with one of seven cell activity proteins, known as G-alpha proteins (2^✔ ✔Trusted Source
Ligand and G-protein selectivity in the κ-opioid receptor

Go to source).

The next-generation medications will need to be designed with the appropriate kind of G-alpha protein in mind, as this will help to precisely target location and cell function by determining the specific shape of the opioid receptor so the drug only reduces pain without affecting other body functions.

For the current study, the researchers used cryogenic electron microscopy to visualize the structure of the kappa opioid receptor. They first needed to flash freeze the receptors, which were bound to a hallucinogenic drug with one of two of the traditional G-alpha proteins.

They then used a different drug to see how the kappa opioid receptor interacted with two other types of G-alpha proteins; one of these G-alpha proteins is found only in the central nervous system and the other is used to detect taste and smell (3^✔ ✔Trusted Source
Molecular insights into the biased signaling mechanism of the µ-opioid receptor

Go to source).

Advertisement

This change in position played an active role in determining the shape of the kappa opioid receptor and thus what drug bound the best to it. These findings ultimately could have implications for how new drugs will be designed.

Researchers face an enormous challenge in developing safer pain-reliever drugs since they will need to target both the correct opioid receptor as well as the appropriate G-alpha protein. Studies like this help to develop the next generation of engineered small molecule drugs that are less addictive.

Advertisement

References:

1. New Technologies for Elucidating Opioid Receptor Function - (https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(16)00002-X)
2. Ligand and G-protein selectivity in the κ-opioid receptor - (https://www.nature.com/articles/s41586-023-06030-7)
3. Molecular insights into the biased signaling mechanism of the µ-opioid receptor - (https://www.cell.com/molecular-cell/fulltext/S1097-2765(21)00611-0)

Source-Eurekalert