Elsevier

Biochemical Pharmacology

Volume 92, Issue 3, 1 December 2014, Pages 448-456
Biochemical Pharmacology

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

https://doi.org/10.1016/j.bcp.2014.09.015Get rights and content
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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.

Keywords

μOR-δOR heteromer
Anti-diarrhea
Eluxadoline
Loperamide
Irritable bowel syndrome

Abbreviations

GI
gastrointestinal
IBS-d
irritable bowel syndrome with diarrhea
μOR
mu opioid receptor
δOR
delta opioid receptor
βgal
beta-galactosidase
GTPγS
guanosine 5′-O-(3-thiotriphosphate)
DAMGO
[d-Ala2, N-MePhe4, Gly-ol]-enkephalin
CB1R
cannabinoid receptor type1
AT1R
angiotensin II receptor type 1
ELISA
enzyme-linked immunosorbent assay
EC50
50% effective concentration
Emax
maximum effective concentration
WT
wild-type
−/−
knockout
eGFP
enhanced green fluorescent protein

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