Pain relief without side effects and addiction

Science -- October 21, 2022: Opioids have a similar pain-relieving effect to new medicines that stimulate adrenalin receptors rather than opioid receptors, but without the drawbacks like respiratory depression and addiction.

Friedrich-Alexander-Universität Erlangen-Nürnberg. "Pain relief without side effects and addiction: Better than opiates: Researchers use adrenaline receptors for highly-effective analgesics." ScienceDaily. ScienceDaily, 19 October 2022. .

worldwide research team at Friedrich-Alexander-Universität Erlangen-Nürnberg, under the direction of the Chair of Pharmaceutical Chemistry, produced this (FAU). Their discoveries—which have just been made public in the scholarly journal Science—mark an important step in the evolution of non-opioid pain treatment.

Addiction is caused by opiates, not by new substances.

Although they are a blessing for people with excruciating pain, they also have harmful side effects: Opioids, especially morphine, can make people feel sick, lightheaded, and constipated. They can also frequently slow breathing, which can induce respiratory failure. Opiates are also addictive; for instance, painkillers are a major contributor to the drug issue in the USA.

Researchers throughout the world are looking for alternative analgesics to combat the opioids' undesirable medical and social impacts. One of these researchers is Professor Dr. Peter Gmeiner, Chair of Pharmaceutical Chemistry. Prof. Gmeiner and an international team of researchers identified an active compound in 2016 that binds to well-known opioid receptors and provides analgesia comparable to morphine, while not sharing any chemical properties with opiates. "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."

Adrenaline receptors rather than opioid receptors in the new strategy

Currently, Peter Gmeiner is following a lead that appears to be quite promising: Now, Gmeiner and a group of scientists from Erlangen, China, Canada, and the USA are focusing on a brand-new receptor called the alpha 2A adrenergic receptor, which is in charge of binding adrenaline. Already, several analgesics including brimonidine, clonidine, and dexmedetomidine target this receptor. Dexmedetomidine reduces pain but has a potent sedative effect, thus its use is limited to intensive care units in hospitals and is unsuitable for a wider range of patient populations, according to Gmeiner.

The goal of the research group is to identify a pharmacological substance that activates the central nervous system receptor without having any sedative effects. The researchers searched a virtual library of more than 300 million readily available chemicals for molecules that physically matched the receptor but did not share chemical properties with any recognized drugs. Around 50 molecules were chosen for synthesis and testing after a series of intricate virtual docking simulations, and two of these met the required standards. They possessed excellent bonding properties, activated only specific protein sub-types, and consequently a very narrow range of cellular signal pathways, in contrast to dexmedetomidine's response to a far greater variety of proteins. 

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."

Pain alleviation in animal models without sedation

The researchers were able to create agonists that created high concentrations in the brain and efficiently decreased the experience of pain in studies with animal models by further refining the identified molecules, for which exceptionally high-resolution cryo-electron microscopic imaging was used. According to several experiments, the analgesic effect was caused by docking on the receptor, says Gmeiner. We are very happy that none of the novel compounds induced drowsiness, even at doses that were significantly greater than those needed to alleviate pain.

Being able to successfully separate sedation from analgesic effects is a significant step in the development of non-opioid pain relievers, especially given how simple it is to produce and give patients the newly discovered agonists orally. Prof. Gmeiner, however, has to dash any expectations of swiftly becoming widely used 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."

Source Credit:

Friedrich-Alexander-Universität Erlangen-Nürnberg. "Pain relief without side effects and addiction: Better than opiates: Researchers use adrenaline receptors for highly-effective analgesics." ScienceDaily. ScienceDaily, 19 October 2022. .

WNCTIMES by Marjorie Farrington