Oliceridine (TRV130) was designed to optimize opioid receptor pharmacology to deliver an improved analgesic profile, and has been granted Breakthrough Therapy designation by the FDA. Oliceridine is the first μ‑receptor G protein pathway selective modulator (μGPS), a biased ligand targeting the μ‑opioid receptor. In preclinical studies, TRV130 activated the mu opioid G protein receptor pathway, in a manner similar to strong opioids such as morphine and fentanyl, and like these drugs oliceridine was a powerful analgesic. Unlike those drugs, in cell‑based studies oliceridine did not engage the β‑arrestin pathway, which has been shown in other preclinical studies to inhibit morphine analgesia and promote mediate morphine‑induced constipation, respiratory depression, and analgesic tolerance(1,2).
In preclinical studies, oliceridine was more potent than morphine, and it reached peak analgesia faster. Oliceridine caused less gastrointestinal dysfunction than morphine at equivalent analgesic doses. Oliceridine also showed an improved therapeutic index for analgesia to respiratory depression compared with morphine(3,4). These studies suggested that oliceridine may offer improved pain relief with lower safety and tolerability effects compared to currently approved opioid analgesics.
1. Bohn, L, et al. Enhanced Morphine Analgesia in Mice Lacking β-Arrestin 2. Science 286: 2495-2498, 1999. View on PubMed.
2. Raehal, K, et al. Morphine Side Effects in β-Arrestin 2 Knockout Mice. J Pharm Exp Therap 314: 1195-1201, 2005. View PDF.
3. DeWire SM et al. A G protein-biased ligand at the mu opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013 Mar;344(3):708‑17. View PDF.
4. Chen X.T. et al. Structure-Activity Relationships and Discovery of a G Protein Biased Mu Opioid Receptor Ligand, TRV130, for the Treatment of Acute Severe Pain. J. Med. Chem. 2013. View PDF.
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