In this blog series I’ve talked a lot about the potential of Salvia in the treatment of depression, addiction and pain. I also examined the molecular pharmacology of Salvinorin A, the main psychedelic constituent in Salvia. Throughout these posts, I’ve discussed how Salvinorin A itself is not ideal for therapy due to its short duration of action and the intense psychedelic effects it induces. As such, scientists are currently trying to create compounds that are based on Salvinorin A, but with additional desirable qualities, such as a longer duration of action and affinity for other receptors.

Here I’ll summarise three recent papers that have created interesting compounds based on Salvinorin A that may have diverse therapeutic applications. The development of these compounds shows how quickly Salvinorin A research is progressing, and brings us one step closer to producing amazing therapeutic applications from this unique plant.

Simonson et al 2015

As we’ve talked about before, Salvinorin A has potential to be used as a treatment of addiction. But Salvinorin A itself is not ideal for therapy; it is metabolised quickly in the body so doesn’t last long enough to be useful, and its psychedelic effects may be counter-productive to therapy. Here, Simonson and colleagues investigate a compound that is similar enough to Salvinorin A to still bind to the kappa-opioid receptor (KOR), but with a longer duration.

The compound is called Mesyl Sal B, and is created by replacing a carbonyl group with a mesylate group at the C2 location (figure 1). The authors thought that this small alteration to the structure of Salvinorin A might change the way the compound is metabolised.

Figure 1 - Salvinorin-aFigure 1 - Mesyl Sal B

Figure 1: Mesyl Sal B is a promising derivative of Salvinorin A that retains its painkilling and anti-addictive properties but with a longer duration of action.

When they compared the painkilling effects of Salvinorin A and Mesyl Sal B in mice, they found that Mesyl Sal B had painkilling effects that lasted longer than Salvinorin A; this suggests that Mesyl Sal B was working in a similar way to Salvinorin A but resisted being broken down better than Salvinorin A.

Since the authors are interested in the therapeutic application of Salvinorin A in the treatment of addiction, they then looked at the tried and tested model of cocaine self-administration in rats. After training rats to become addicted to cocaine, then removing them from cocaine for a period of time, they found that rats were less likely to become re-addicted to cocaine if they’d been given a dose of Mesyl Sal B first; similar to what we see with Salvinorin A. Although the authors don’t directly compare the anti-addictive effects of Mesyl Sal B with Salvinorin A, it’s a promising finding; the altered compound seems to retain the beneficial qualities of Salvinorin A.

Riley et al 2014

This group is also interested in finding a therapy for cocaine addiction using Salvinorin A as a foundation. This time, the modification to Salvinorin A occurs on the furan ring of the molecule (figure 2). The authors say that most other scientists have focused on replacing the furan ring entirely; but these guys more interested in adding different types of chemical groups to the ring in an attempt to find a form of Salvinorin A that is more long-lived, but just as active at the KOR.

Riley and colleagues looked at over 40 different chemical additions to the furan ring of Salvinorin A, and analysed the ability of these compounds to bind to the KOR. They picked the three most promising compounds, called 2, 24 and 36 (figure 2), and administered them to rats that were undergoing the same cocaine relapse model used in the above study. They found that all three of these compounds reduced the potential for rats to become re-addicted to cocaine, mirroring the qualities of Salvinorin A.

Figure 2

Figure 2: these three altered forms of Salvinorin A all retain anti-addictive effects.

Again, however, there is no direct comparison to Salvinorin A, so we can’t be sure how effective these compounds are. All Riley and colleagues are showing is that these compounds retain their ability to bind to the KOR and retain anti-addictive properties. The next step will be to show whether they are active for longer or exhibit reduced side effects.

Polepally et al 2014

Another potential application of Salvinorin A is as a unique non-addictive painkiller. The ideal Salvinorin A derivative would be active at both the KOR and the mu-opioid receptor (MOR); that would give it anti-addictive properties (from the KOR) and painkilling properties (mainly from the MOR). This is where Polepally and colleagues come in, as they try to develop compounds that bind to both the KOR and the MOR.

All changes to Salvinorin A were made at the C2 location, of varying length and complexity. Various compounds showed affinity for both the KOR and the MOR. The most promising change, an addition of a phenyl ring (figure 3), resulted in a molecule called 5a that bound to both the KOR and the MOR with high affinity. Although this compound showed reduced affinity for the KOR compared to Salvinorin A, its increased affinity for the MOR is extremely promising.

The next step for these compounds is to determine their painkilling properties, to see if they could become viable analgesics that have the same anti-addictive properties as Salvinorin A. This would be a huge breakthrough in the treatment of pain, despite still being a long way off.

Figure 3

Figure 3: this altered form of Salvinorin A has affinity for both the mu- and kappa-opioid receptors, meaning it may be a promising compound for developing a non-addictive painkiller.

Conclusions

These are just the three most recent papers published by the many hundreds of scientists currently researching Salvinorin A in an attempt to create therapies for drug addiction and pain. This amazing natural product could one day be hailed as the source of an addiction-free painkiller, or the foundation for an effective anti-addiction therapy. Who knows what other breakthroughs Salvia could bring?

References

Polepally PR, Huben K, Vardy E, Setola V, Mosier PD, Roth BL, Zjawiony JK (2014) Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor. European journal of medicinal chemistry 85:818-829.

Riley AP, Groer CE, Young D, Ewald AW, Kivell BM, Prisinzano TE (2014) Synthesis and kappa-opioid receptor activity of furan-substituted salvinorin A analogues. Journal of medicinal chemistry 57(24):10464-10475.

Simonson B, Morani AS, Ewald AW, Walker L, Kumar N, Simpson D, Miller JH, Prisinzano TE, Kivell BM (2015) Pharmacology and anti-addiction effects of the novel kappa opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A. British journal of pharmacology 172(2):515-531.