TRV0109101 is a μ-opioid peptide receptor (MOPR) selective agonist ( K D = 70 nM) with blood-brain barrier permeability. TRV0109101 selectively promotes G protein signaling pathway coupling while reducing the recruitment of β-arrestin. TRV0109101 inhibits opioid-induced mechanical hyperalgesia and induces antinociceptive tolerance. TRV0109101 is applicable for pain-related research [1].
In Vivo, TRV0109101 (20 mg/kg/day; s.c.; continuous infusion; 7 days) does not promote opioid-induced mechanical allodynia in male C57BL/6 mice but does induce antinociceptive tolerance[1]. TRV0109101 (20-40 mg/kg; s.c.; twice daily (days 1-3), single double dose (day 4); 5 days) does not induce opioid-induced mechanical allodynia in male C57BL/6 mice but does induce antinociceptive tolerance[1]. TRV0109101 (20 mg/kg; s.c.; twice daily; 7 days) rapidly reverses mechanical allodynia in male C57BL/6 mice, though antinociceptive tolerance still develops[1]. TRV0109101 (1-3 mg/kg; s.c.; twice daily) rapidly and fully reverses induced mechanical allodynia in male C57BL/6 mice, though antinociceptive tolerance still develops[1]. TRV0109101 (0.1-10 mg/kg; s.c.; single dose) produces dose-dependent antinociception in the mouse 56°C hot plate assay, with an ED50 of 1.1 mg/kg[1]. TRV0109101 (1-20 mg/kg; s.c.; single dose) produces dose-dependent inhibition of fecal boli accumulation in male C57BL/6 mice, with an ED50 of 6.3 mg/kg[1]. TRV0109101 (1-20 mg/kg; s.c.; single dose) produces dose-dependent inhibition of colonic motility in male C57BL/6 mice, with an ED50 of 9.4 mg/kg[1].
In Vitro, TRV0109101 acts as a potent, G protein-biased, MOPR-selective agonist in HEK-293 cells, with an EC50 of 10 nM for cAMP inhibition[1]. TRV0109101 (41 nM-10 μM; 5 min) interacts with the orthosteric ligand binding site of human MOPR in HEK-293 cells, with an apparent KD of 70 nM in competition with DAMGO for β-arrestin2 recruitment[1].
References:
[1]. Koblish M, et al. TRV0109101, a G Protein-Biased Agonist of the µ -Opioid Receptor, Does Not Promote Opioid-Induced Mechanical Allodynia following Chronic Administration. J Pharmacol Exp Ther. 2017;362(2):254-262.
[2]. Chen XT, et al. Structure-activity relationships and discovery of a G protein biased μ opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain. J Med Chem. 2013;56(20):8019-8031.
In Vivo, TRV0109101 (20 mg/kg/day; s.c.; continuous infusion; 7 days) does not promote opioid-induced mechanical allodynia in male C57BL/6 mice but does induce antinociceptive tolerance[1]. TRV0109101 (20-40 mg/kg; s.c.; twice daily (days 1-3), single double dose (day 4); 5 days) does not induce opioid-induced mechanical allodynia in male C57BL/6 mice but does induce antinociceptive tolerance[1]. TRV0109101 (20 mg/kg; s.c.; twice daily; 7 days) rapidly reverses mechanical allodynia in male C57BL/6 mice, though antinociceptive tolerance still develops[1]. TRV0109101 (1-3 mg/kg; s.c.; twice daily) rapidly and fully reverses induced mechanical allodynia in male C57BL/6 mice, though antinociceptive tolerance still develops[1]. TRV0109101 (0.1-10 mg/kg; s.c.; single dose) produces dose-dependent antinociception in the mouse 56°C hot plate assay, with an ED50 of 1.1 mg/kg[1]. TRV0109101 (1-20 mg/kg; s.c.; single dose) produces dose-dependent inhibition of fecal boli accumulation in male C57BL/6 mice, with an ED50 of 6.3 mg/kg[1]. TRV0109101 (1-20 mg/kg; s.c.; single dose) produces dose-dependent inhibition of colonic motility in male C57BL/6 mice, with an ED50 of 9.4 mg/kg[1].
In Vitro, TRV0109101 acts as a potent, G protein-biased, MOPR-selective agonist in HEK-293 cells, with an EC50 of 10 nM for cAMP inhibition[1]. TRV0109101 (41 nM-10 μM; 5 min) interacts with the orthosteric ligand binding site of human MOPR in HEK-293 cells, with an apparent KD of 70 nM in competition with DAMGO for β-arrestin2 recruitment[1].
References:
[1]. Koblish M, et al. TRV0109101, a G Protein-Biased Agonist of the µ -Opioid Receptor, Does Not Promote Opioid-Induced Mechanical Allodynia following Chronic Administration. J Pharmacol Exp Ther. 2017;362(2):254-262.
[2]. Chen XT, et al. Structure-activity relationships and discovery of a G protein biased μ opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain. J Med Chem. 2013;56(20):8019-8031.