Without side effects or addiction, pain relief is available without any drugs.
Philipp Seemann, a doctoral candidate at FAU and co-lead researcher, was among the researchers who discovered substances that provide effective pain relief without the addiction and sedative side effects of current drugs. (Image: FAU/Stefan Lober)
Researchers at FAU have found that adrenaline receptors can be used to create highly effective analgesics.
The new substances, which activate adrenaline receptors rather than opioid receptors, have the same pain-relieving effects as opiates but without any of their negative side effects, such as respiratory depression or addiction. The research was carried out by a team of international researchers led by the Chair for Pharmaceutical Chemistry at FAU. The findings of the team, which were published in Science, a renowned scientific journal, mark a significant milestone in the development and use of non-opioid methods for pain relief.
Opiates cause addiction; new substances do not.
These drugs are often a godsend for those who suffer from severe pain. However, they can have some serious side effects. Opioids and morphine in particular can cause nausea, constipation, and dizziness. They can also cause breathing problems that may even lead to respiratory failure. Opiates are also addictive. A large percentage of the US drug problem is due to pain medications.
Researchers around the globe are looking for alternatives to opioids in order to combat their negative medical and social effects. Professor Dr. Peter Gmeiner is one of the researchers. Gmeiner says, "We're concentrating on the molecular structure of the receptors that dock onto the pharmaceutical substance". It is only by understanding these at the atomic scale that we will be able to develop safe and effective active substances.
Adrenaline receptors as opposed to opioid receptors
Peter Gmeiner has been following a promising lead: "Many nonopioid receptors are involved with pain processing, but only a few of these alternatives have yet to be validated for use as therapies", he says. Gmeiner, along with a team from Erlangen, China, and Canada, have focused their attention on a new receptor responsible for binding to adrenaline, the alpha-2A adrenergic receptor. Some analgesics already target this receptor, such as brimonidine, clonidine, and dexmedetomidine. Gmeiner: "Dexmedetomidine is a powerful sedative that relieves pain but is only suitable for patients in intensive care.
The research consortium's goal is to identify a chemical compound that activates the receptors of the central nervous system but does not have a sedative effect. Researchers searched a virtual library with more than 300,000,000 molecules to find compounds that are physically similar to the receptor but not chemically related. A series of virtual docking simulations led to the selection of around 50 molecules for testing and synthesis. Two of these met the criteria. They were able to bond well but only activated certain sub-types of proteins and therefore a very select set of signal pathways. Dexmedetomidine, on the other hand, responds to an even wider range of proteins.
Animal models of pain relief without sedation
The researchers optimized the molecules identified using cryo-electron microscopy, which allowed them to synthesize agonists with high concentrations of molecules in the brain and reduce the pain sensation in animal models. Gmeiner explains that "different tests confirmed docking at the receptor is responsible for the analgesic effects." We are especially pleased that none of the compounds caused sedation, even at doses that were much higher than would be needed for pain relief.
The separation of analgesic and sedative properties is a major milestone in the development and manufacture of non-opioid medications, particularly as the newly identified agonists are relatively easy to produce and to administer orally to patients. Professor Gmeiner, however, has to put an end to any hopes for a rapid and widespread use of the drug in human medicine. "We are still dealing with basic research." It takes time and money to develop medication. There are strict controls as well as significant funding. These results are still very encouraging."
