Science Non-Opioid Painkiller Milestones: Reduced Pain, No Side Effects and Addiction!

The new substance that activates adrenergic receptors instead of opioid receptors has analgesic effects similar to opioids, but without the negative effects
such as respiratory depression and addiction.
This is the result
of an international research team led by the Chair of Medicinal Chemistry at Friedrich-Alexander-Universit?t Erlangen-Nürnberg (FAU).
Their findings, which have been published in the prestigious scientific journal Science, are a milestone
in the development of non-opioid painkillers.

Opiates are addictive, new substances are not

They are a boon for patients suffering from severe pain, but they also have serious side effects: opioids, especially morphine, can cause nausea, dizziness and constipation, and often slow breathing and even respiratory failure
.
In addition, opiates are addictive — for example, in the United States, a large percentage of drug problems are caused by
painkillers.

To address the unnecessary medical and social impact of opioids, researchers around the world are looking for alternative painkillers
.
Professor Peter Gmeiner is one of
these researchers.
Gmeiner said: "We are particularly concerned about the molecular structure
of the receptors that dock with the drug.
Only when we understand this at the atomic level can we develop effective and safe active substances
.
"In 2016, Professor Gmeiner, in collaboration with an international research team, discovered an active substance that binds to known opioid receptors and provides the same degree of pain relief as morphine, although it bears no chemical resemblance to opioids
.

New approach: adrenergic receptors instead of opioid receptors

Gmeiner is currently working on a study that seems very promising: "Many non-opioid receptors are involved in pain management, but only a small fraction of such alternatives have been validated for therapeutic
use.
" Gmeiner and his team of researchers from China, Canada and Erlangen in the United States are now turning their attention to a new receptor responsible for binding to adrenaline, the α-2A adrenergic receptor
.
There are already a number of painkillers that target this receptor, such as brimonidine, clonidine, and dexmedetomidine
.
Gmeiner: "Dexmedetomidine relieves pain but has a strong sedative effect, which means that its use is limited to intensive care in hospitals and is not suitable for a wider patient population
.
"

The team's goal was to find a compound
that activates central nervous system receptors without producing a sedative effect.
In a virtual library of more than 300 million different and easily accessible molecules, the researchers looked for compounds
that were physically matched to the receptor but chemically unrelated to known drugs.
After a series of complex virtual docking simulations, about 50 molecules were selected for synthesis and testing, two of which met the expected standards
.
They have good binding properties and activate only specific protein isoforms, so they are a highly selective group of cell signaling pathways, while dexmedetomidine acts
on a wider range of proteins.

There is no analysis in animal models

By further optimizing the identified molecules, the researchers used extremely high-resolution cryo-electron microscopy imaging, which was able to synthesize agonists that produce high concentrations in the brain and effectively reduce pain sensation
in animal model studies.
Gmeiner explains: "Various tests confirm that docking with the receptor is responsible for
the pain-relieving effect.
" "We are particularly pleased that none of these new compounds produced a sedative effect, even at doses much
higher than those needed for pain relief.
"

The successful separation of analgesic and sedative effects is a milestone in the development of non-opioid analgesics, especially as newly discovered agonists are relatively easy to manufacture and take orally to patients
.
However, Professor Gmeiner had to dismiss the hope that this rapid widespread application in human medicine: "We are still discussing basic research
.
The development of drugs is strictly controlled and takes a long time, in addition to a
large amount of money.
However, these results still leave us very optimistic
.
”