1 research outputs found
Structure–Activity Relationships and Discovery of a G Protein Biased μ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]({2-[(9<i>R</i>)‑9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the Treatment of Acute Severe Pain
The concept of “ligand bias”
at G protein coupled
receptors has been introduced to describe ligands which preferentially
stimulate one intracellular signaling pathway over another. There
is growing interest in developing biased G protein coupled receptor
ligands to yield safer, better tolerated, and more efficacious drugs.
The classical μ opioid morphine elicited increased efficacy
and duration of analgesic response with reduced side effects in β-arrestin-2
knockout mice compared to wild-type mice, suggesting that G protein
biased μ opioid receptor agonists would be more efficacious
with reduced adverse events. Here we describe our efforts to identify
a potent, selective, and G protein biased μ opioid receptor
agonist, TRV130 ((<i><b>R</b></i>)-<b>30</b>). This novel molecule demonstrated an improved therapeutic index
(analgesia vs adverse effects) in rodent models and characteristics
appropriate for clinical development. It is currently being evaluated
in human clinical trials for the treatment of acute severe pain