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.

中文翻译：

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吗啡肽的环状衍生物在胃肠道中具有抗转运作用并减轻小鼠的腹痛。

背景技术肠易激综合症（IBS）是一种具有反复出现的胃肠道（GI）症状的慢性疾病：运动性改变和腹痛。由于内源性阿片类药物系统参与疼痛感知和胃肠道蠕动的控制，因此阿片类药物已被认为是IBS的有希望的疗法。在以前的研究中，我们观察到吗啡肽衍生物P-317（Dmt-cyclo-（D-Lys-Phe-D-Pro-Asp）-NH2）具有可用于IBS的有希望的功能。在该项目中，我们测试了基于环吗啡肽的结构修饰：氟化（化合物1）或肽键还原（化合物2）是否可提高药理作用。方法我们评估了在生理（胃肠道转运）和病理生理（蓖麻油腹泻，压力诱发的运动过度，内脏痛）条件下小鼠胃肠道系统中测试的衍生物。结果两种化合物均延长了胃肠道转运。化合物1和P-317抑制结肠的上消化道转运和运动。化合物2保持不活泼。与对照组相比，化合物1和P-317抑制了应激小鼠的过度运动，并延迟了急性腹泻。仅P-317发挥镇痛作用。与P-317相似，测试的衍生物均不影响运动活性。结论化合物1在小鼠胃肠道中与P-317同样有效。肽键的还原降低了化合物2的活性。氟化似乎是增加吗啡肽类似物在胃肠道中作用的有效方法。与对照组相比，化合物1和P-317抑制了应激小鼠的过度运动，并延迟了急性腹泻。仅P-317发挥镇痛作用。与P-317相似，测试的衍生物均不影响运动活性。结论化合物1在小鼠胃肠道中与P-317同样有效。肽键的还原降低了化合物2的活性。氟化似乎是增加吗啡肽类似物在胃肠道中作用的有效方法。与对照组相比，化合物1和P-317抑制了应激小鼠的过度运动，并延迟了急性腹泻。仅P-317发挥镇痛作用。与P-317相似，测试的衍生物均不影响运动活性。结论化合物1在小鼠胃肠道中与P-317同样有效。肽键的还原降低了化合物2的活性。氟化似乎是增加吗啡肽类似物在胃肠道中作用的有效方法。