Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers

Abstract

Eluxadoline, an orally active mixed μ opioid receptor (μOR) agonist δ opioid receptor (δOR) antagonist developed for the treatment of diarrhea-predominant irritable bowel syndrome, normalizes gastrointestinal (GI) transit and defecation under conditions of novel environment stress or post-inflammatory altered GI function. Furthermore, compared to loperamide, which is used to treat non-specific diarrhea, the effects of eluxadoline on GI transit occur over a wider dosage range. However, the mechanisms of action of eluxadoline are unclear. In this study, we compared the ability of eluxadoline and loperamide to activate G-protein- and β-arrestin-mediated signaling at μOR homomers or μOR-δOR heteromers in heterologous cells. We also examined the ability of both compounds to reduce castor oil induced diarrhea in wild type (WT) and mice lacking δOR. We find that eluxadoline is more potent than loperamide in eliciting G-protein activity and β-arrestin recruitment in μOR expressing cells. However, in cells expressing μOR-δOR heteromers, the potency of eluxadoline is higher, but its maximal effect is lower than that of loperamide. Moreover, in these cells the signaling mediated by eluxadoline but not loperamide is reduced by μOR-δOR heteromer-selective antibodies. We find that in castor oil-induced diarrhea eluxadoline is more efficacious compared to loperamide in WT mice, and δOR appears to play a role in this process. Taken together these results indicate that eluxadoline behaves as a potent μOR agonist in the absence of δOR, while in the presence of δOR eluxadoline’s effects are mediated through the μOR-δOR heteromer.

Eluxadoline for the treatment of diarrhoea-predominant irritable bowel syndrome

“…[51] The absence of opioid receptors habituation to eluxadoline is another pharmacokinetic strength, based on the μ-and δ-opioid receptor heterodimer formation by the drug. [39] Male sex, unlike other 5-TH3 acting antagonist alosetron [14] for IBS-D is not a limitation in drug prescription, allowing easier and wider use of eluxadoline in clinical practice.…”

“…[37,38] These findings taken together suggest that μ-and δ-opioid receptors can interact; this interaction can be realized through allosteric formation of heterodimers (Box 1). Thus, the pharmaceutical industry started to manufacture mixed μ-opioid agonist and δ-opioid receptors antagonists, such as eluxadoline, potentially usable for both pain and diarrhea treatment in gastroenterological disorders characterized by these two issues, such as IBS-D. [39] …”

“…[40,41] In vitro cell cultures and animal models of wild-type and μ-or δ-opioid receptors knock-out mice treated with castor-oil to induce diarrhea [39] demonstrated that eluxadoline interacts with opioid receptors also via receptor heterodimerization specifically in the gut, reducing intestinal contractility, and stress-induced acceleration of GI transit and enhancing analgesia without constipation development. [41] 6.…”

Drug discovery approaches to irritable bowel syndrome

“…Acute castor oil-induced diarrhea is a popular model of enhanced GI transit [97][98][99] and was used to characterize morphine and loperamide anti-diarrheal effects. Croton oil is an inflammatory irritant when given intracolonically and the resulting acute increased transit is also ameliorated by OR agonists [100] and cannabinoid receptor agonists [101].…”

Eluxadoline: a promising therapy that raises many questions

“…Eluxadoline, however, represents a unique addition to the IBS-D therapeutic milieu and clinicians are just gaining experience with it since it became available in January of 2016. Eluxadoline is an orally administered, minimally absorbed mixed opioid receptor modulator, acting as a mu (μOR) and kappa opioid receptor agonist and delta opioid receptor (δOR) antagonist (1). It is thought that the μOR agonist component of eluxadoline reduces propulsive gastrointestinal motility and chloride secretion while the δOR antagonist component reduces both abdominal pain and opposes μOR activation, tending to 'normalize' bowel function rather than constipate (2).…”