Ligand bias at G protein coupled receptors describes preferential ligand signaling via one intracellular pathway over another (e.g., G protein over β-arrestin). Targeting and developing biased G protein coupled receptor ligands could provide an opportunity to develop safer and more efficacious drugs. The efforts to identify a μ-opioid receptor G protein biased ligand with increased analgesic efficacy and less severe adverse side effects compared to morphine will be described. Optimization of a lead chemical series resulted in the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2[(9<i>R</i>)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel μ-opioid receptor biased ligand that elicits robust G protein signaling, of similar potency and efficacy to morphine, but with less β-arrestin engagement and receptor internalization. Compared to morphine in rodent models, TRV130 demonstrated an improved therapeutic index of analgesia vs. adverse effects, including gastrointestinal dysfunction and respiratory suppression. The compound is currently being evaluated in human clinical trials for the treatment of postoperative pain. Early clinical findings in experimental models revealed that TRV130 produced greater analgesic effect than morphine at doses with less reduction in respiratory drive and less severe nausea, supporting a biased ligand approach to developing improved medicines.

Discovery of TRV130, a G protein biased agonist of the μ-opioid receptor, for the treatment of acute severe pain

249th National Meeting (2015)

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