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Discovery & Development Drug Delivery

Eliminating Side Effects In Silico

“My group has studied the biology and pharmacology of opioid receptors on peripheral sensory neurons for over 25 years”, says Christoph Stein, Director, Department of Anesthesiology and Surgical Intensive Care Medicine, Charité – Universitätsmedizin Berlin. “Our aim has always been to find mechanisms and opioid receptor ligands that can be developed into drugs which inhibit pain, without also eliciting typical adverse effects of conventional opioids, such as apnea, addiction, sedation or constipation.”

“From our previous work we knew that selective activation of opioid receptors can produce powerful pain relief. These analgesic effects are particularly strong in pain caused by tissue injury and inflammation. So, together with mathematicians at the Zuse Institute Berlin, we began using computer simulations to examine the interaction between opioid ligands and receptors in normal and inflamed environments,” says Stein. The group discovered that low pH – as found in damaged/inflamed tissue – led to stronger binding of opioid ligands to peripheral opioid receptors. To benefit from this effect, the team designed a new compound – called NFEPP – that, because of its low acid dissociation constant, selectively activates peripheral µ-opioid receptors (MORs) at lower pH, limiting its effect to injured tissue (1)(2)(3). “These new compounds avoid the detrimental side effects of both conventional opioids and nonsteroidal analgesics,” 
adds Stein.

Stein is aware of his group’s potential contribution to a solution to the opioid crisis in the US – but cautions that new drugs alone are not the answer: “Improved pain medication will not erase this crisis; that will require joint efforts by politicians, medical societies, healthcare providers, insurers, researchers and the pharma industry. However, new drugs without deleterious side effects will be an important step in the right direction.”

The team now plans to investigate the interaction of opioid ligands and receptors in inflamed environments in more detail, and is seeking partners or investors from pharma to push their new compound towards phase I and II clinical trials.

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  1. A Rodriguez-Gaztelumendi et al., “Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain”, Pain, [Epub ahead of print] (2018). DOI: 10.1097/j.pain.0000000000001328.
  2. V Spahn et al., “A nontoxic pain killer designed by modeling of pathological receptor conformations”, Science, 355, 966–969 (2017). DOI: 10.1126/science.aai8636
  3. V Spahn et al., “Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist”, Scientific Reports, 8, 8965 (2018). DOI: 10.1038/s41598-018-27313-4
About the Author
Roisin McGuigan

I have an extensive academic background in the life sciences, having studied forensic biology and human medical genetics in my time at Strathclyde and Glasgow Universities. My research, data presentation and bioinformatics skills plus my ‘wet lab’ experience have been a superb grounding for my role as a Deputy Editor at Texere Publishing. The job allows me to utilize my hard-learned academic skills and experience in my current position within an exciting and contemporary publishing company.

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