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. To tackle the unwanted medical and social effects of opioids, researchers all over the world are searching for alternative analgesics. Prof 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”, said Prof 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
Prof 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 explained. Prof Gmeiner and his international team of researchers have 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 dexmedetomidine, brimonidine, and clonidine. “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,” explained Prof Gmeiner.
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.
PAIN RELIEF WITHOUT SEDATION IN ANIMAL MODELS
By further optimising the identified molecules, for which extremely high-resolution cryo-electron microscopic imaging was used, the researchers were able to synthesise 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,” explained Prof 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.”
Full study: https://www.science.org/doi/10.1126/science.abn7065
