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



## VSsupport (Feb 12, 2008)

[TD]
*Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers.*

Biochem Pharmacol. 2014 Sep 24;

Authors: Fujita W, Gomes I, Dove LS, Prohaska D, McIntyre G, Devi LA

Abstract
Eluxadoline, an orally active mixed Î¼ opioid receptor (Î¼OR) agonist Î´ opioid receptor (Î´OR) 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 nonspecific 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 Î²-arrestin-mediated signaling at Î¼OR homomers or Î¼OR-Î´OR 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 Î´OR. We find that eluxadoline is more potent than loperamide in eliciting G-protein activity and Î²-arrestin recruitment in Î¼OR expressing cells. However, in cells expressing Î¼OR-Î´OR 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 Î¼OR-Î´OR heteromer-selective antibodies. We find that in castor oil-induced diarrhea eluxadoline is more efficacious compared to loperamide in WT mice, and Î´OR appears to play a role in this process. Taken together these results indicate that eluxadoline behaves as a potent Î¼OR agonist in the absence of Î´OR, while in the presence of Î´OR eluxadoline's effects are mediated through the Î¼OR-Î´OR heteromer.

PMID: 25261794 [PubMed - as supplied by publisher]

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