Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers.
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Fujita W, Gomes I, Dove LS, Prohaska D, McIntyre G, Devi LA
Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers.
Biochem Pharmacol. 2014 Dec 1;92(3):448-56. doi: 10.1016/j.bcp.2014.09.015. Epub 2014 Sep 28.
- PubMed ID
- 25261794 [ View in PubMed]
- Abstract
Eluxadoline, an orally active mixed mu opioid receptor (muOR) agonist delta opioid receptor (deltaOR) 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 beta-arrestin-mediated signaling at muOR homomers or muOR-deltaOR 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 deltaOR. We find that eluxadoline is more potent than loperamide in eliciting G-protein activity and beta-arrestin recruitment in muOR expressing cells. However, in cells expressing muOR-deltaOR 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 muOR-deltaOR heteromer-selective antibodies. We find that in castor oil-induced diarrhea eluxadoline is more efficacious compared to loperamide in WT mice, and deltaOR appears to play a role in this process. Taken together these results indicate that eluxadoline behaves as a potent muOR agonist in the absence of deltaOR, while in the presence of deltaOR eluxadoline's effects are mediated through the muOR-deltaOR heteromer.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Eluxadoline Delta-type opioid receptor Protein Humans YesAntagonistDetails Eluxadoline Mu-type opioid receptor Protein Humans YesAgonistDetails