Summary: Researchers have developed a new substance that activates adrenalin receptors rather than opioid receptors to help relieve chronic pain. The new compounds have similar pain-relieving qualities as opioids but do not appear to induce respiratory depression or addiction.
Source: Friedrich-Alexander-Universität Erlangen-Nürnberg
New substances that activate adrenalin receptors instead of opioid receptors have a similar pain-relieving effect to opiates, but without the negative aspects such as respiratory depression and addiction.
This is the result of research carried out by an international team of researchers led by the Chair of Pharmaceutical Chemistry at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU).
Their findings, which have now been published in the renowned scientific journal Science, are a milestone in the development of non-opioid pain relief.
Opiates cause addiction, new substances do not
They are a blessing for patients suffering from severe pain, but they also have serious side effects: Opioids, and above all morphine, can cause nausea, dizziness and constipation and can also often cause slowed breathing that can even result in respiratory failure.
In addition, opiates are addictive – a high percentage of the drug problem in the USA is caused by pain medication, for example.
In order to tackle the unwanted medical and social effects of opioids, researchers all over the world are searching for alternative analgesics.
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 researchers, 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.
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. Image is in the public domain
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.
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 a milestone in the development of non-opioid pain medication, especially as 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.”
Abstract
Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor
Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α2A-adrenergic receptor (α2AAR), seeking new α2AAR agonists chemotypes that lack the sedation conferred by known α2AAR drugs, such as dexmedetomidine.
We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential Gi and Go signaling. Experimental structures of α2AAR complexed with two of these agonists confirmed the docking predictions and templated further optimization.
Several compounds, including the initial docking hit ‘9087 [mean effective concentration (EC50) of 52 nanomolar] and two analogs, ‘7075 and PS75 (EC50 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation.
These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.
I am a 45-year-old male and broke my lower back when I was 17 and when I was in my early thirties I ruptured a disc in my upper the middle back I’ve been reinjured my my lower back again in my early thirties and my upwards and middle back for a second time I have been battling back pain for most of my life and only in the Last 5 Years my back pain has become almost embearable. I cannot take prescription opioids due to battling prescription opioid Addiction on and off for over 25 years so I’m basically left unable to treat my back pain so if this company is looking for people to use in human trials I would be one of the first to volunteer.
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I’m right there with you. I’m 67 and it’s highly unlikely these meds will be available in my lifetime, so I would LOVE to participate in any trial that may come up while I’m still on this earth. I’ve had multiple back and neck surgeries. I currently have 4 bulging lumbar discs, extensive arthritis, severe stenosis, and bone spurs. I also have a plate and rods that extend from my head into my upper back and recently learned there are 4 loose screws. I can’t describe the pains that shoot into my head and also into my shoulder and hand. One screw, in particular, is causing stroke-like symptoms. I get double-vision that sometimes lasts up to 2-3 days if I move my head slightly in a certain direction. The doctor says I need surgery NOW, but unfortunately, 3 surgeons told me that I’m no longer a candidate for surgery because I have so much metal in my neck that intubating me is too risky. What am I supposed to do? I’m already suffering, and the doctor acknowledged that the symptoms are going to get even worse. It seems that every week a new symptom crops up or a current symptom gets worse.
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Hey Gina , interesting! How did they find the screw was loose? Having some same issues you can private message if I like on fb Yvette Janney Hodges
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My dad had this pain in his face Dr treated it with a medication used for siezures and it went away. In your face is called a triamentic nerve. It can be fixed
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My wife suffering from back pain and pain medication is not helping 🙏 consider my wife tanking you
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All medicine that relives pain can be addictive if a person has an addictive personality. Don’t blame the drug. It’s the person who is responsible for their addiction. I know of people who take Opiods at prescribed levels and do not abuse them at all.
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I’m sorry Kai, but you clearly have never spent a long period on opioid medication because if you had you would realise that there are two types of addiction, physical addiction and psychological addiction. Opioid medication causes the former given enough time on the medication in question, stopping the medication without very gradual step-down of the dosage causing serious and even life threatening withdrawal effects. This is due to the fact that the body begins to produce more mu-opioid receptors in order to better bind with the opioid medication, when you stop taking the medication, the receptors are starved and the body begins experiencing severe withdrawal symptoms – this has nothing to do with the patients personality and if they have an addictive personality or not, simply due to biochemistry and the effect of starving a body that has biochemically changed to better absorb and use the drug in question and the resultant change that is necessary to sneak that person’s biochemistry back to normal again when it is time to come off of the medication. Please therefore do not speak about something you have insufficient knowledge about in the first place, it is because of people like you that long term pain patients are denied the pain medication they need to live a relatively liveable life. As a long term pain patient myself (14 years) who has seen people who have not been as lucky as me to have a skilled pain team and a GP who isn’t afraid to prescribe long term despite the current climate of negativity towards long term opioid prescription, it is people like you that have resulted in those individuals not getting the pain relief they require and having to either fall back on the street equivalent or have been forced to take their own life because they simply could not handle the pain anymore. Think before you type in future please.
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You actually have insufficient knowledge and should educate yourself before typing. There is a HUGE difference between an addict and being physically dependent on medication. And it’s not just opioids that cannot be stopped abruptly–many others, including anti-seizure medications, heart medications, and diabetic medications also can’t be abruptly stopped because the body will undergo harmful withdrawal symptoms. I had been on and off high doses of pain meds for over 30 years and had never abused them or turned to the streets. You also either have no knowledge on “addictive personalities,” or you know someone who overdosed and don’t want to admit the person was an addict, although there is no shame in admitting this as it is a legitimate medical condition. Please educate yourself before you criticize someone who is obviously more knowledgeable than you.
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I can so relate to this response. I too have been on opioids for chronic pain since 2009. Many failed surgeries resulting in more nerve damage let alone the psychological challenge of constant surgical or medication failures and or intolerances expecting to become pain free after the next surgery promised to be a fix. Many in the medical profession shun you after their systemic failures. Contemplating life to continue living with chronic debilitating pain is so common. I’ve spent a fortune on the so called best physicians all to no avail. I live in fear when either I’ll become completely immune to all opioids, none that work as they once did or my Drs will stop prescribing using the reason I’m too good to turn into a drug dependant junkie of sorts
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I have been suffering severe pain in neck a d over head as result of whiplash. I have had many treatments, and am extremele sensitive to medication. At moment I take about 9 Stilpane pills as well as about 4 mg ativan. Not helping. At night its worse and I also have burning mouth syndrome. Can you give advice please. Heila Janse van Rensburg
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God help chronic pain people, we need relief,Ian 70yr old experimental scoliosis patient for Dr. Herrington and need help so bad,no quality of life, Can’t find Doc who are even interested in helping me, please, please bring this to light asap. I just would like 1 day without pain. Thank you
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Pain control is good. Fact impaired smearing of safe and effective opiate Rx medicine is unnecessary and shouldn’t be in this article.
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I know of a woman, 61 , who has been struggling for 10+ years with chronic facial pain. She is at her wits end. Diagnosed with atypical facial pain she has tried all the meds. Seems like opiates help but…. Are you looking at human trials soon? Please advise, she would be interested.
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