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 ß-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the µ-opioid receptor (MOR) to G proteins, but not ß-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 ß-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.
Subject(s)
Analgesics/pharmacology , GTP-Binding Proteins/metabolism , Gastrointestinal Tract/drug effects , Morphine/pharmacology , Receptors, Opioid, mu/metabolism , Respiratory System/drug effects , Animals , Arrestins/metabolism , Cell Line , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/drug therapy , Gastrointestinal Diseases/metabolism , HEK293 Cells , Humans , Ligands , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/metabolism , Respiratory Tract Diseases/chemically induced , Respiratory Tract Diseases/drug therapy , Respiratory Tract Diseases/metabolism , Signal Transduction/drug effects , beta-Arrestin 2 , beta-ArrestinsABSTRACT
Two parallel synthetic methods were developed to explore the structure-activity relationships (SAR) of a series of potent opioid agonists. This series of tropanylidene benzamides proved extremely tolerant of structural variation while maintaining excellent opioid activity. Evaluation of several representative compounds from this series in the mouse hot plate test revealed potent antinociceptive effects upon oral administration.
Subject(s)
Analgesics , Benzamides , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Benzamides/chemical synthesis , Benzamides/chemistry , Mice , Molecular Structure , Pain Measurement/drug effects , Structure-Activity RelationshipABSTRACT
A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c, exhibited extremely high affinity for the delta opioid receptor with excellent selectivity versus the micro opioid receptor. They were full agonists at the delta opioid receptor, as assessed by stimulation of GTPgammaS binding, and displayed antinociceptive activity.
Subject(s)
Analgesics, Opioid/pharmacology , Benzamides/pharmacology , Receptors, Opioid, delta/agonists , Analgesics, Opioid/chemistry , Benzamides/chemistry , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Structure-Activity RelationshipABSTRACT
The tertiary amide delta opioid agonist 2 is a potent antinociceptive agent. Compound 2 was metabolized in vitro and in vivo to secondary amide 3, a potent and selective micro opioid agonist. The SAR of a series of N-alkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides was examined.