title: A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine.
abstract: The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in β-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the μ-opioid receptor (MOR) to G proteins, but not β-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel MOR G protein-biased ligand. In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less β-arrestin recruitment and receptor internalization. In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. TRV130 successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology. These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain.
authors.affiliation: Trevena Inc., 1018 West 8th Ave., King of Prussia, PA 19406, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: DeWire
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: David H
authors.initials: DH
authors.lastname: Rominger
authors.forename: Guodong
authors.initials: G
authors.lastname: Liu
authors.forename: Conrad L
authors.initials: CL
authors.lastname: Cowan
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Graczyk
authors.forename: Xiao-Tao
authors.initials: XT
authors.lastname: Chen
authors.forename: Philip M
authors.initials: PM
authors.lastname: Pitis
authors.forename: Dimitar
authors.initials: D
authors.lastname: Gotchev
authors.forename: Catherine
authors.initials: C
authors.lastname: Yuan
authors.forename: Michael
authors.initials: M
authors.lastname: Koblish
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lark
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Violin
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects*; D012140:Respiratory Tract Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D000700:Analgesics; C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D019390:Arrestins; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009020:Morphine; D019204:GTP-Binding Proteins