title: 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.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Wakako
authors.initials: W
authors.lastname: Fujita
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ivone
authors.initials: I
authors.lastname: Gomes
authors.affiliation: Furiex Pharmaceuticals, Inc., 3900 Paramount Parkway, Suite 150, Morrisville, NC 27560, USA.
authors.forename: Leonard S
authors.initials: LS
authors.lastname: Dove
authors.affiliation: Furiex Pharmaceuticals, Inc., 3900 Paramount Parkway, Suite 150, Morrisville, NC 27560, USA.
authors.forename: David
authors.initials: D
authors.lastname: Prohaska
authors.affiliation: Furiex Pharmaceuticals, Inc., 3900 Paramount Parkway, Suite 150, Morrisville, NC 27560, USA.
authors.forename: Gail
authors.initials: G
authors.lastname: McIntyre
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: Lakshmi.devi@mssm.edu.
authors.forename: Lakshmi A
authors.initials: LA
authors.lastname: Devi
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002368:Castor Oil / Q000009:adverse effects; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008024:Ligands; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D055503:Protein Multimerization; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D007093:Imidazoles; D008024:Ligands; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D000071557:beta-Arrestins; C583636:eluxadoline; D010649:Phenylalanine; D008139:Loperamide; D002368:Castor Oil
keywords: Anti-diarrhea; Eluxadoline; Irritable bowel syndrome; Loperamide; μOR-δOR heteromer