Safer analgesics by modulation of the k-opioid receptor

With a prevalence of 20-30% worldwide, chronic pain affects more people than heart disease, cancer and diabetes combined, and will certainly continue to grow as the population ages. Incapacitating pain is a constant backdrop in daily life, resulting in personal suffering, high healthcare costs and economic burden for the society. Pain relief and management can be achieved via binding and activation of opioid receptors by opioid analgesics. While currently available opioids, such as morphine, oxycodone and fentanyl, are agonists at the mu-opioid receptor (MOR), and effectively reduce pain, they cause also serious side effects (i.e. constipation, respiratory depression, sedation, nausea, tolerance and dependence). Prescription opioid misuse and addiction is a rapidly escalating epidemic in the past years, resulting in increased opioid-related overdose deaths. Therefore, research efforts are needed towards overcoming the limitations of present therapies, with the final goal to improve treatment efficacy, patient compliance and to reduce complications. The rationale of the planned research is based on (a) the kappa-opioid receptor (KOR) an opioid receptor subtype that can be targeted to effectively reduce pain without the risks of physical dependence and addictive potential associated with currently used MOR agonists, (b) the recent elucidation of the active structure of KOR, and (c) the contemporary concept of biased agonism and the therapeutic promise of biased agonism for better pain treatment. Recent data revealed the exciting prospect that biased KOR agonists, preferentially activating G protein signaling, may be identified as a new class of analgesic drugs with fewer adverse effects, and without liability for addiction and abuse. The present project comprises basic research as computational and experimental work undertaken in the fields of pain research and KOR pharmacology aiming to identify novel, effective, safe and nonaddictive scientifically proven opioid drugs at the KOR with target-oriented pharmacology (i.e. G protein-biased agonism) for pain treatment, and to assess functional selectivtiy and structural and molecular determinants that can form the basis for an improvement of the benefit/risk index. The outcomes of this project will expand the understanding on ligand-receptor interaction, molecular mode of action and KOR-mediated signaling pathways towards identifying better tolerated and more efficacious analgesic drugs. Besides the scientific aspect, this project entails medical, social and economic perspectives on a long-term basis. The outlooks of this project are of high relevance due to the increasing number of patients suffering from chronic pain. For this project, expert teams from the two universities in Berlin and Innsbruck will combine their expertise. Multidisciplinary, synergistic strategies will be applied to achieve the goals of the planned research, where state-of the-art methodologies will be used ranging from computational modeling to pharmacological and disease animal models, suitable to endow the proposed research with high translational potential.

With a prevalence of 20-30% worldwide, chronic pain affects more people than heart diseases, cancer and diabetes combined, and will certainly continue to grow as the population ages. Incapacitating pain is a constant backdrop in daily life, resulting in personal suffering, high healthcare costs and economic burden for the society. Pain relief can be achieved via binding and activation of opioid receptors by opioid analgesics. While currently available opioids, such as morphine, oxycodone and fentanyl, are agonists at the mu-opioid receptor (MOR), and effectively reduce pain, they cause also serious side effects. Prescription opioid misuse and addiction is a rapidly escalating epidemic in the past years, resulting in increased opioid-related overdose deaths. Research efforts are needed towards overcoming the limitations of present therapies, with the final goal to improve treatment efficacy, patient compliance and to reduce complications. Preclinical and clinical evidence has shown that effective analgesia also occurs when the kappa-opioid receptor (KOR) is activated, without the risks of physical dependence and abuse liability. This project combined computational and experimental work in the fields of pain research and KOR pharmacology, and identified ligands at the KOR with target-oriented pharmacology (i.e. G protein-biased agonism) and improved pharmacology and safety profiles, as potential new pain therapeutics. These compounds, small molecules and peptides, represent innovative structures which bind, activate and have G protein-biased agonist profile at the KOR. Their analgesic efficacy in experimental animal pain models was demonstrated together with the reduced propensity for adverse effects. Detailed studies on the structural, molecular and functional mechanisms were performed to establish the basis for the improvement of the benefit/risk index. Additionally, discovery of new chemotypes and peptide-based ligands as novel KOR antagonists is of high significance given the promise of KOR blockade in the treatment of neuropsychiatric disorders, and the comorbidity of chronic pain with depression, anxiety and addiction in pain patients. The results of this project expand the understanding on ligand-receptor interaction, molecular mode of action and KOR-mediated signaling pathways towards identifying better tolerated and more efficacious drugs for treatment of pain and other human diseases where the KOR plays a key role. Multidisciplinary and synergistic approaches were combined in this project to achieve the specific aims, ranging from the molecular in silico and in vitro levels to in vivo systems, with bioinformatics and computational systems and state-of-the-art biochemical, pharmacological and disease animal models, suitable to endow the investigations with high translational potential. Overall, this project offers new therapeutic solutions by introducing innovative G protein-biased KOR agonists producing beneficial analgesia, without the undesirable adverse effects of conventional opioid analgesics, and potential for development of KOR therapeutics for other medical applications.