BACKGROUND & PURPOSELoperamide is a selective m opioid receptor agonist acting locally in the gastrointestinal (GI) tract as an effective anti-diarrhoeal but can cause constipation. We tested whether modulating m opioid receptor agonism with d opioid receptor antagonism, by combining reference compounds or using a novel compound ('MuDelta'), could normalize GI motility without constipation. EXPERIMENTAL APPROACHMuDelta was characterized in vitro as a potent m opioid receptor agonist and high-affinity d opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following ex vivo and in vivo experiments: guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport and upper GI tract transit, entire GI transit or faecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post-inflammatory). Colonic d opioid receptor immunoreactivity was quantified. KEY RESULTSd Opioid receptor antagonism opposed m opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically-mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up-regulated d opioid receptor expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and faecal output to control levels over a wide dose range, whereas loperamide had a narrow dose range. MuDelta and loperamide reduced upper GI transit in the post-inflammatory model. CONCLUSIONS AND IMPLICATIONSMuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea-predominant irritable bowel syndrome.

These results demonstrate that PROK1 has oral prokinetic and secretogogue activity and that it acts on the intestinal mucosa via PK-R1 and prostaglandin receptors to mediate these effects.

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ABSTRACT:We have discovered a novel series of 4-azetidinyl-1-arylcyclohexanes as CCR2 antagonists. Divergent SAR studies on hCCR2 and hERG activities led to the discovery of compound 8d, which displayed good hCCR2 binding affinity (IC 50 , 37 nM) and potent functional antagonism (chemotaxis IC 50 , 30 nM). It presented an IC 50 of >50 μM in inhibition of the hERG channel and had no effect on the QTc interval up to 10 mg/kg (i.v.) in anesthetized guinea pig and dog CV studies. It also displayed high selectivity over other chemokine receptors and GPCRs, and amendable oral bioavailability in dogs and primates. In a thioglycollate-induced inflammation model in hCCR2KI mice, it had ED 50 of 3 mg/kg on inhibition of the influx of leukocytes, monocytes/macrophages, and T-lymphocytes.