Scientists have identified new substances that have a similar pain-relieving effect to opiates, but without the negative aspects such as respiratory depression and addiction. Instead of activating opioid receptors, they work by stimulating adrenalin receptors. This is the result of research carried out by an international team of researchers led by the Chair of Pharmaceutical Chemistry at FAU. Their findings are a milestone in the development of non-opioid pain relief and have recently been published in the renowned scientific journal Science.
“Opiates” vs. “opioids”
Although these terms are often used interchangeably they are different: Opiates refer to natural opioids such as heroin, morphine and codeine. Opioids refer to all natural, semisynthetic, and synthetic opioids.
Opiates cause addiction, new substances do not
While opiates are a blessing for many patients suffering from severe pain, they also have serious side effects. Opioids, and above all morphine, can cause nausea, dizziness, and constipation. They can also often cause slowed breathing that can even result in respiratory failure. Moreover, opiates are addictive – a high percentage of the drug problem in the United States is caused by pain medication, for example.
All over the world researchers are searching for alternative analgesics (pain relieving medications) in order to tackle the unwanted medical and social effects of opioids. Prof. Dr. Peter Gmeiner, Chair of Pharmaceutical Chemistry is one of these researchers.
“We are focusing particularly on the molecular structures of the receptors that dock onto the pharmaceutical substances,” says Gmeiner. “It is only when we understand these on the atomic level that we can develop effective and safe active substances.”
Collaborating with an international team of scientists, Prof. Gmeiner discovered an active substance in 2016 that bonds to known opioid receptors and that offers the same level of pain relief as morphine, even though it has no chemical similarity to opiates.
New approach: Adrenaline receptors instead of opioid receptors
Peter Gmeiner is currently following a lead that seems very promising: “Many non-opioid receptors are involved in pain processing, but only a small number of these alternatives have as yet been validated for use in therapies,” he explains.
Gmeiner and a team of researchers from Erlangen, China, Canada, and the USA have now turned their attention to a new receptor that is responsible for binding adrenaline – the alpha 2A adrenergic receptor. There are already some analgesics that target this receptor such as brimonidine, clonidine, and dexmedetomidine. Gmeiner: “Dexmedetomidine relieves pain, but has a strong sedative effect, which means its use is restricted to intensive care in hospital settings and is not suitable for broader patient groups.”
The aim of the research consortium is to find a chemical compound that activates the receptor in the central nervous system without a sedative effect. In a virtual library of more than 300 million different and easily accessible molecules, the researchers looked for compounds that physically match the receptor but are not chemically related to known medication.
After a series of complex virtual docking simulations, around 50 molecules were selected for synthesis and testing and two of these fulfilled the desired criteria. They had good bonding characteristics, activated only certain protein sub-types, and thus a very selective set of cellular signal pathways, whereas dexmedetomidine responds to a significantly wider range of proteins.
An agonist is a drug or substance that binds to a receptor inside a cell or on its surface and causes the same action as the substance that normally binds to the receptor.
Pain relief without sedation in animal models
By further optimizing the identified molecules, for which extremely high-resolution cryo-electron microscopic imaging was used, the researchers were able to synthesize agonists that produced high concentrations in the brain and reduced the sensation of pain effectively in investigations with animal models.
“Various tests confirmed that docking on the receptor was responsible for the analgesic effect,” explains Gmeiner. “We are particularly pleased about the fact that none of the new compounds caused sedation, even at considerably higher doses than those that would be required for pain relief.”
The successful separation of analgesic properties and sedation is an important milestone in the development of non-opioid pain medication. It is especially noteworthy because the newly-identified agonists are comparatively easy to manufacture and administer orally to patients.
However, Prof. Gmeiner has to dampen any hopes of rapid widespread use in human medicine: “We are currently still talking about basic research. The development of medication is subject to strict controls and in addition to significant amounts of funding, it takes a long time. However, these results still make us very optimistic.”
Reference: “Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor” by Elissa A. Fink, Jun Xu, Harald Hübner, Joao M. Braz, Philipp Seemann, Charlotte Avet, Veronica Craik, Dorothee Weikert, Maximilian F. Schmidt, Chase M. Webb, Nataliya A. Tolmachova, Yurii S. Moroz, Xi-Ping Huang, Chakrapani Kalyanaraman, Stefan Gahbauer, Geng Chen, Zheng Liu, Matthew P. Jacobson, John J. Irwin, Michel Bouvier, Yang Du, Brian K. Shoichet, Allan I. Basbaum and Peter Gmeiner, 30 September 2022, Science.