Agata Szymaszkiewicz1, Jakub Włodarczyk1, Marzena Mazur2,3, Jacek Olczak2,3, Jakub Fichna1, Marta Zielińska4. 1. Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland. 2. TriMen Chemicals, Lodz, Poland. 3. OncoArendi Therapeutics SA, Warsaw, Poland. 4. Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland. marta.zielinska@umed.lodz.pl.
Abstract
BACKGROUND: Irritable bowel syndrome (IBS) is a chronic condition with recurring gastrointestinal (GI) symptoms: altered motility and abdominal pain. As endogenous opioid system participates in pain perception and in the control of GI peristalsis, opioids have been proposed as a promising therapy in IBS. In a previous study, we observed that morphiceptin derivative, P-317 (Dmt-cyclo-(D-Lys-Phe-D-Pro-Asp)-NH2), presents promising features to be applied in IBS. In this project, we tested whether modifications in cyclic morphiceptin-based structure: fluorination (compound 1) or peptide bond reduction (compound 2) improve pharmacological effect. METHODS: We evaluated tested derivatives in the mouse GI system under physiological (GI transit) and pathophysiological (castor oil diarrhea, stress-induced hypermotility, visceral pain) conditions. RESULTS: Both compounds prolonged GI transit. Compound 1 and P-317 inhibited upper GI transit and motility of the colon; compound 2 remained inactive. Compound 1 and P-317 inhibited hypermotility in stressed mice and delayed the acute diarrhea in comparison to control. Only P-317 exerted antinociceptive effect. None of tested derivatives, similar to P-317, affected locomotor activity. CONCLUSIONS: Compound 1 is equally effective as P-317 in the mouse GI tract. The peptide bond reduction decreased the activity of compound 2. Fluorination appears to be an efficient way to increase the effects of morphiceptin analogs in the GI tract.
BACKGROUND:Irritable bowel syndrome (IBS) is a chronic condition with recurring gastrointestinal (GI) symptoms: altered motility and abdominal pain. As endogenous opioid system participates in pain perception and in the control of GI peristalsis, opioids have been proposed as a promising therapy in IBS. In a previous study, we observed that morphiceptin derivative, P-317 (Dmt-cyclo-(D-Lys-Phe-D-Pro-Asp)-NH2), presents promising features to be applied in IBS. In this project, we tested whether modifications in cyclic morphiceptin-based structure: fluorination (compound 1) or peptide bond reduction (compound 2) improve pharmacological effect. METHODS: We evaluated tested derivatives in the mouse GI system under physiological (GI transit) and pathophysiological (castor oildiarrhea, stress-induced hypermotility, visceral pain) conditions. RESULTS: Both compounds prolonged GI transit. Compound 1 and P-317 inhibited upper GI transit and motility of the colon; compound 2 remained inactive. Compound 1 and P-317 inhibited hypermotility in stressed mice and delayed the acute diarrhea in comparison to control. Only P-317 exerted antinociceptive effect. None of tested derivatives, similar to P-317, affected locomotor activity. CONCLUSIONS: Compound 1 is equally effective as P-317 in the mouseGI tract. The peptide bond reduction decreased the activity of compound 2. Fluorination appears to be an efficient way to increase the effects of morphiceptin analogs in the GI tract.