Novel opioid antagonists for bowel motility disorders

Opioid therapy for post-operative or chronic pain is frequently associated with severe adverse effects, the most common being bowel dysmotility. The perspectives of the proposed research program are of high relevance due to the high number of patients suffering from debilitating and largely inadequately treated bowel motility disorders associated with opioid treatments or mechanisms like post-operative ileus (POI) and opioid-induced bowel dysfunction (OBD). Theoretical and experimental work will be undertaken to acquire new insights and knowledge in the field of opioid morphinans targeting the peripheral opioid system in the gastrointestinal tract, aiming to identify and to develop scientifically proven novel opioid drugs with reliable target-oriented pharmacological profile, established efficacy and favourable safety profile for the treatment of bowel motility disorders.

Opioid therapy for post-operative or chronic pain is frequently associated with severe adverse effects, the most common being bowel dysmotility. The perspectives of this project are of high relevance due to the high number of patients suffering from debilitating and largely inadequately treated bowel motility disorders associated with opioid treatments or mechanisms like post-operative ileus (POI) and opioid-induced bowel dysfunction (OBD). The rationale of the project is based on the knowledge that opioid receptors modulate intestinal functions including motility and secretion under physiological conditions. Stimulation of mu opioid receptors appears to be primarily involved in impaired gastrointestinal motor function. Theoretical and experimental investigations were performed to attain new insights and knowledge in the field of opioid morphinans targeting the peripheral opioid system in the gastrointestinal tract, aiming to identify and develop scientifically proven novel peripherally acting mu opioid receptor antagonists with reliable target-oriented pharmacological profile, established efficacy and favorable safety profile for the treatment of bowel motility disorders. Combining modern computational approaches with chemical synthetic methods and pharmacological investigations resulted in the development and identification of novel peripherally active mu opioid receptor antagonists with improved benefit/risk ratio as new therapeutics for the treatment of bowel motility disorders, such as POI and OBD. The novel opioid antagonists with peripheral action represent new morphinan derivatives with a zwitterionic moiety which highly increases hydrophilicity of these molecules. Therefore, they are not capable of passing the blood-brain barrier and do not interfere with opioid analgesia. These molecules bind with high affinity and show antagonist activity at the mu receptor, and produce improved gastrointestinal motor function. Increased specificity in the treatment of pathological processes of bowel motility dysfunction should be achieved with the new opioid antagonists in comparison to the currently available drugs. Besides the scientific aspect, this project entails medical, social and economic perspectives in a long-term basis. One is to offer patient relief from bowel motility dysfunction, by introducing more efficient drugs with reduced side effects. The social aspect can be a decrease in sick-listing, which will reduce the social costs. Thus, more effective and well-tolerated pharmacotherapy may facilitate return to professional life and improve work performance. The economic aspect is to open up a new market within the pharmaceutical sector.