In this post I’d like to discuss a natural product that is near and dear to my heart; the oil of the Copaiba genus of trees. The reason this natural product is special to me is because it’s mechanism of action was part of a side project I investigated as a graduate student. During that work, I realized that one of the primary mechanisms of action of Copaiba’s constituents is highly likely to be inhibition of Fatty Acid Binding Proteins (FABPs). Designing and synthesizing inhibitors of FABPs was precisely what I was working on during the majority of my time as a graduate student. Thus, it was quite encouraging to realize there was already a proven natural product with what appears to be exactly the same mechanism of action.
One of the main molecular constituents of Copaiba resins are decalin analogs with a carboxylic acid; in other words, fatty acids. These compounds resemble other ligands of FABPs in several ways, however they have far less aromaticity than synthetic analogs. A highly desirable feature in a true drug, if you ask me. Anyway, looking at the predicted pharmacology of the decalin analogs demonstrates that, within the updated STP, they are indeed predicted to bind to FABP1, FABP4, FABP3, and FABP5. FABP inhibition can result in increased extracellular endocannabinoid concentrations and subsequently increased anti-inflammatory and anti-nociceptive effects. Somehow FABP inhibition does not rank very highly amongst the predicted targets, however within the SEA prediction of Copalic acid and Agathic acid one can see the Retinoic acid receptors within the most likely predicted targets. Retinoic acid receptors are descend from the same evolutionarily ancestor as FABPs, making the possibility of ligand overlap highly likely as well. In that sense, the SEA prediction isn’t totally unreasonable. I would imagine there are some serious differences in the training sets used between STP and SEA that might cause these differences and “blind spots.” The relevance to these results to novel drug discovery targeting FABPs could be interpreted in multiple ways. From one perspective, it is a proof of concept that fatty acids that inhibit FABPs can relieve pain without intoxication and is thus very encouraging. A more cynical perspective is that the maximum potential of FABP inhibitors has already been realized. Online vendors are already fully loaded with Copaiba products touting various benefits. In either case, one must also consider other potential mechanisms of action of Copaiba before seeing the big picture of how Copaiba is relevant to modern medicine.
Looking beyond FABPs, there are several very interesting targets of the major constituents of Copaiba. Cunabic acid and Kaurenoic acid both resemble steroids in addition to resembling fatty acids. Interestingly, one of their associated targets include cortisone, cortisol, and prostaglandin metabolizing enzymes like 11-beta-hydroxysteroid dehydrogenases. Cortisol manipulation is more complicated to verify as antinociceptive since it can be both proinflammatory but also antinociceptive depending on where in the body its concentration is being manipulated. However, prostaglandins are well verified as pro-inflammatory so the inhibition of their synthesis is exceptionally well validated for anti-nociception. Yet another possible mechanism is the inhibition of the nuclear receptors peroxisome proliferator activated receptor (PPAR) family. These transcription factors manage which inflammatory proteins are expressed, and thus their inhibition can also produce anti-inflammatory effects. Last but not least is the possibility that neurotransmitter modulation enables the effects of Copaiba extracts. In particular, Eudesmene and Gamma Bisabolone are predicted to interact with the sodium dependent noradrenaline and dopamine transporters in addition to the norepinephrine and serotonin transporters. These mechanisms are also well validated in their potential for anti-nociceptive effects, especially within the peripheral nervous system.
Looking at the big picture, Copaiba has a very interesting combination of predicted pharmacological action. Generally speaking, multiple mechanisms are likely to attribute for its remarkable anti-inflammatory and anti-nociceptive effect with FABP inhibition being a top contender. Yet if this mechanism is really what yields the benefits of Copaiba extract, that means that the Truxillic Acid Monoester FABP inhibitors I made as a graduate student may have a far less unique potential as a new medicine.
