Develop painkillers with fewer side effects

People suffering from chronic pain are often dependent on medications in the opioid class with sometimes considerable side effects. As a result, in recent years the search for safer alternatives has been the focus of new drug discovery.

As part of an international study led by MedUni Vienna, an opioid-like molecule was developed which, as shown in animal models, can effectively relieve pain but with fewer unwanted side effects. Researchers have developed a computer-assisted workflow that holds enormous potential for improving the search for drug-like substances and thus drug therapies. The study was recently published in Natural communications.

Prescription opioid medications commonly used in painkillers can lead to drug dependence with serious consequences, including life-threatening respiratory depression, especially when the opioid is overdosed or used in combination with sedatives (such as alcohol or sleeping pills). The international research team led by Christian Gruber with first author Edin Muratspahić from the Institute of Pharmacology at MedUni Vienna focused on developing new possibilities for finding alternative remedies for pain.

Opioid painkillers such as fentanyl or morphine act primarily on the brain’s µ-opioid receptor, which is associated with serious side effects. That’s why researchers from Austria, Australia and the United States have been looking for drug candidates that bind to a related receptor, the κ-opioid receptor, another receptor important for regulating pain in the body. human.

New avenues for drug development

To specifically design chemical compounds with a high affinity for their drug target, researchers used a new computer-aided design method. The “de novo” design approach has now been used to generate compounds that target the G protein-coupled receptor (abbreviation GPCR) family, which constitutes one of the most important pharmacological drug targets for approved therapies.

Using a combination of “de novo” designs, pharmacological and structural analyses, only four compounds needed to be synthesized and experimentally validated to ultimately identify a promising drug-like molecule: DNCP-β-NalA(1) (“De novo circular peptide-β-naloxamine”).

As the study illustrates, this newly developed opioid-like compound had a potent analgesic effect in animal models without triggering associated adverse symptoms such as sedation or dysphoria. Thanks to the targeted activation of individual cellular signaling pathways of the κ-opioid receptor, this drug candidate thus promises better tolerability with a simultaneous reduction in side effects.

“During our study, we developed a workflow that facilitates the discovery and development of new painkillers,” explains study leader Christian Gruber, emphasizing the scope of the research work.

The “de novo” design process offers a significant improvement over existing drug discovery methods commonly used in pharmaceutical research, such as structure-based virtual library or molecule-based high-throughput screens. Since the κ-opioid receptor is a prototypical GPCR, the method could be applied, in the future, for the development of better drugs with reduced side effects for other GPCRs that are important in treatment, e.g. cardiovascular, metabolic or mental diseases. diseases.

The potential of currently discovered molecules as a treatment for pain will need to be studied and confirmed by other studies. “Even if successful, it may be several years before they are approved for clinical use. Our discovery should nevertheless give hope to many patients suffering from chronic pain,” says Gruber.