TRV130: Another Structurally Novel Opioid With Interesting Properties

[SeenSoFar]

Hello everyone! Sorry to be on an opioid posting spree this last little while, but I've come across quite a few interesting ones recently... And here's another one! TRV130 is totally novel structurally, and has some features which suggest it may be less likely to induce tolerance and dependence than classical opioids. The structure, the abstracts of the papers about it, and the links to said papers are below. I'd really like to know what people have to say about this one, as it seems to be quite promising! Anyway, here's the goods!

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

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 ((R)-30). 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.​

Full Paper Available Here Free​

A G Protein-Biased Ligand at the μ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine​

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 β-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the μ-opioid receptor (MOR) to G proteins, but not β-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 β-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.​

Full Paper Available Here Free​

First Clinical Experience With TRV130: Pharmacokinetics and Pharmacodynamics in Healthy Volunteers​

TRV130 is a G protein-biased ligand at the µ-opioid receptor. In preclinical studies it was potently analgesic while causing less respiratory depression and gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. A first-in-human study was conducted with ascending doses of TRV130 to explore its tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers. TRV130 was well-tolerated over the dose range 0.15 to 7 mg administered intravenously over 1 hour. TRV130 geometric mean exposure and Cmax were dose-linear, with AUC0–inf of 2.52 to 205.97 ng h/mL and Cmax of 1.04 to 102.36 ng/mL across the dose range tested, with half-life of 1.6–2.7 hours. A 1.5 mg dose of TRV130 was also well-tolerated when administered as 30, 15, 5, and 1 minute infusions. TRV130 pharmacokinetics were modestly affected by CYP2D6 phenotype: clearance was reduced by 53% in CYP2D6 poor metabolizers.TRV130 caused dose- and exposure-related pupil constriction, confirming central compartment µ-opioid receptor engagement. Marked pupil constriction was noted at 2.2, 4, and 7 mg doses. Nausea and vomiting observed at the 7 mg dose limited further dose escalation. These findings suggest that TRV130 may have a broad margin between doses causing µ-opioid receptor-mediated pharmacology and doses causing µ-opioid receptor-mediated intolerance.​

 

[sekio]

Well, seeing as it's currently being investigated in humans, that bodes well.

has some features which suggest it may be less likely to induce tolerance and dependence than classical opioids.

This made me roll my eyes. Since when have we ever discovered a mu-opioid ligand that doesn't produce tolerance and dependence somewhat? Isn't this what people said about... every opioid invented since people discovered you could esterify morphine? I certainly remember people said that about e.g. tramadol.

TRV130 was also well-tolerated when administered as 30, 15, 5, and 1 minute infusions. [...] TRV130 caused dose- and exposure-related pupil constriction, confirming central compartment µ-opioid receptor engagement. Marked pupil constriction was noted at 2.2, 4, and 7 mg doses. Nausea and vomiting observed at the 7 mg dose limited further dose escalation.

"Well-tolerated" is one way to put it 8) I wonder if it's orally active, too. A compound with hydromorphone type potency that is well absorbed orally would be a fun time...

It is somewhat concerning that at much higher doses, some of these compounds are targets for hERG & other cardiac channels and the analogues of the title compound could induce arrythmias in rats at doses many times higher than their opioid activity. But at least the compound being used in human trials has been optimized against that kind of stuff, and you shouldn't see problems until easily 200x the opioid dose...

 

[endotropic]

This made me roll my eyes. Since when have we ever discovered a mu-opioid ligand that doesn't produce tolerance and dependence somewhat? Isn't this what people said about... every opioid invented since people discovered you could esterify morphine? I certainly remember people said that about e.g. tramadol.

How are you going to get a new mu-opioid approved if you don't argue that it solves the tolerance/dependence problem? You're certainly not going to convince anyone that they're more efficacious than what we have already. So yea agreed on the 8)

 

[SeenSoFar]

Well, seeing as it's currently being investigated in humans, that bodes well.

has some features which suggest it may be less likely to induce tolerance and dependence than classical opioids.

This made me roll my eyes. Since when have we ever discovered a mu-opioid ligand that doesn't produce tolerance and dependence somewhat? Isn't this what people said about... every opioid invented since people discovered you could esterify morphine? I certainly remember people said that about e.g. tramadol.

From my understanding of things, it's specifically the fact that this compound recruits β-arrestin to a much lesser degree than the conventional opioids. I believe that this particular property has been shown to inhibit the formation of tolerance and slows the development of dependence. Who knows if these features will carry over to humans or not, but apparently another side-effect of it's low β-arrestin efficacy is reduced constipation, which is always a bonus!

TRV130 was also well-tolerated when administered as 30, 15, 5, and 1 minute infusions. [...] TRV130 caused dose- and exposure-related pupil constriction, confirming central compartment µ-opioid receptor engagement. Marked pupil constriction was noted at 2.2, 4, and 7 mg doses. Nausea and vomiting observed at the 7 mg dose limited further dose escalation.

"Well-tolerated" is one way to put it 8) I wonder if it's orally active, too. A compound with hydromorphone type potency that is well absorbed orally would be a fun time...

Yes, I'll bet they "tolerated" the intravenous administration of a class of compounds known to cause massive rushes of euphoria when administered intravenously quite well . From what I've read on the site of Trevena (the company who is developing it,) it most likely has a very poor oral bioavailability. They don't come out and say as much clearly, at least in all the material I have read, but they are developing another compound called TRV734. I cannot find a skeletal formula or IUPAC name for it, but the information that they do give claims it is supposed to follow the same line of thinking, a μ-opioid selective agonist which has very low β-arrestin efficacy. The difference is, TRV130 is specifically stated to be for IV use against post-operative pain, whereas TRV734 is said to be for oral treatment of moderate to severe acute or chronic pain. To me, this means that TRV130 probably doesn't have very decent oral bioavailability, or there is some other reason for not taking it orally.

It is somewhat concerning that at much higher doses, some of these compounds are targets for hERG & other cardiac channels and the analogues of the title compound could induce arrythmias in rats at doses many times higher than their opioid activity. But at least the compound being used in human trials has been optimized against that kind of stuff, and you shouldn't see problems until easily 200x the opioid dose...

Yeah I did notice that too. That is specifically why they continued the development of the compound instead of settling for (R)-19. The risk of long-QT syndrome was too great with that series, so they moved on to the next series, from which TRV130 emerged. I doubt you will ever reach the dose of this compound required to mess with your QT interval, around 200x the dose for an opiate naive individual. That would have to be some bad-ass tolerance to get up to a dose that high. Actually though, a lot of opioids also mess with the QT interval, and it doesn't stop people from using them.