Peripheral opioid receptors, a target for gut diseases

The present project comprises basic research as theoretical and experimental work undertaken to acquire new insights and knowledge in the field of opioid morphinans targeting the peripheral opioid system in the gastrointestinal tract aiming to improve the understanding of physiological and pathological processes in chronic inflammation of the gut. The goal of the research program is to identify and develop scientifically proven opioid drugs with reliable target-oriented pharmacological and favorable safety profiles as potential therapeutic agents for inflammatory bowel disease (IBD), a chronic and incapacitating gastrointestinal disease that is still inadequately treated resulting in a poor quality of patient`s life. Besides the classical use of mu opioid receptor agonists (e.g. morphine) as analgesics, they exert inhibitory effects on intestinal motility and secretion. Such opioid compounds (e.g. loperamide) are clinically used in the symptomatic treatment of diarrhea. Mu opioid receptors are found in the central and peripheral nervous system and are expressed in various peripheral tissues including the gut and immune cells. In vitro experimental studies have shown that mu opioid agonists modulate lymphocyte proliferation and production of inflammatory and immunoregulatory cytokines. In vivo evidence of the regulatory immune functions of mu opioid agonists has been described in several models of autoimmune and inflammatory diseases. The rationale of the planned research program is based on recent experimental findings that selective agonists of peripheral mu opioid receptors have preventive and therapeutic intestinal anti-inflammatory effects in in vivo models of colitis, through activation of peripheral mu opioid receptors in the gut, and regulation of cytokine production and T cell proliferation. Therefore, peripherally acting mu opioid agonists were proposed as potential therapeutic agents for the treatment of IBD. On this basis, we aim to direct our research towards identification of non-peptidic selective peripherally restricted mu opioid receptor agonists as new therapeutic molecules in IBD. Within the research strategy, we also aim to investigate the molecular and immunological mechanisms that contribute to inflammatory processes of IBD and which can be used as "druggable" targets to modulate the altered gastrointestinal immune response associated with IBD. Applying in silico computational approaches, peripherally acting mu opioid agonists of the 14-alkoxymorphinan series will be designed to exhibit increased hydrophilicity by targeting critical positions in the morphinan structure. Combining theoretical and experimental methodologies, it is planned (i) to explore in depth the chemical structural requirements of the 14-alkoxymorphinan series of opioids using computer-aided molecular drug design approaches (ii) to elaborate superior computational and chemical synthetical methods, (iii) to achieve advanced understanding of structure-activity relationship for opioid morphinans focusing on the peripheral opioid receptors, (iv) to gain further knowledge on the involvement of opioid receptors in physiological and pathological processes of gut inflammation as well as (v) to perform research focused on peripheral opioid mechanisms by employing non- peptidic opioids with high affinity and increased selectivity at the opioid receptor, and peripheral selective activity. Multidisciplinary and synergistic approaches including innovative and highly efficient methods will be applied to achieve the goals of the research program which will include in silico drug design, synthesis, in vitro biological, pharmacological and immunological characterization and in vivo experimental testing of the new opioid compounds together with mechanistic studies. The potential benefit of peripherally acting mu agonists in IBD will be the combination of analgesic, anti-inflammatory and anti-diarrheal activities.

Inflammatory bowel diseases (IBD, such as ulcerative colitis and Crohn`s disease) are a family of chronic inflammatory disorders of the gastrointestinal (GI) tract. To date, the prevailing means of treating IBD have been unable to offer satisfactory long-term solutions, stressing the need for research for new and better therapeutic strategies. Moreover, this research area is of high relevance due to an ever increasing number of patients suffering from chronic inflammatory GI diseases, such as IBD. 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 GI 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 IBD. Combining computational approaches with synthetical work resulted in the development of new opioid ligands interacting with the mu opioid receptor. These molecules bound with high affinity and showed agonist activity at the mu receptor, and produced immunosuppressive effects. The derivatives showed high analgesic potency and were considerably more potent than morphine. Unlike morphine, these substances act only in the periphery, and therefore do not show the usual centrally mediated adverse effects. Efficacy in experimental models of colitis, by having preventive and therapeutic intestinal anti-inflammatory effects, was demonstrated for this class of molecules. The benefit of such peripherally acting mu opioid agonists developed during the project is the combination of anti-inflammatory and antinociceptive properties, highlighting the potential of these peripheral mu opioid agonists as novel therapeutics for the treatment of human IBD. The newly developed mu opioid agonists acting in the periphery have the potential to considerably improve the quality of life of patients suffering of IBD. Besides the scientific aspect, this project entails medical, social and economic perspectives in a long-term basis. One is to offer patient relief from chronic and incapacitating inflammatory GI diseases, by introducing more efficient drugs with reduced side effects. The social aspect can be a decrease in sick-listing and early retirement because of these conditions, 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.