Cyclic derivatives of morphiceptin possess anti-transit effect in the gastrointestinal tract and alleviate abdominal pain in mice

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)-NH 2 ), 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.