“Previous studies reported that the acid congener of the cannabinoids, cannabidiolic acid, was approximately 1000 times more effective than the neutral congener, cannabidiol, in alleviating emesis.
The biological actions of cannabinoids were proposed to be mediated by the enhancement of somatodendritic 5-HT1A receptors. However, to date, the potential mechanism that may be involved in the enhancement of the 5-HT1A activity by the acid congener is still lacking. To address this gap, molecular docking and molecular dynamics simulations were performed on different pairs of neutral and acidic cannabinoids in a human 5-HT1A receptor model.
Analyses showed that simulated cannabinoid acids (cannabidiolic acid and tetrahydrocannabivarinic acid) and tetrahydrocannabivarin were preferentially bound at the allosteric site of 5-HT1A and were able to maintain the receptor in its active state when a full agonist, R(+)-8-OH-DPAT, was bound at the orthosteric site. Importantly, these results also suggest that the strong activity of cannabidiolic acid is not due to its strong affinity for the 5-HT1A receptor but its positive allosteric modulation of the agonist activity on 5-HT1A, presumably by blocking the exit of the orthosteric ligand, hence promoting continuous activation of the receptor. This study also demonstrates that cannabidiol and both neutral and acidic cannabigerol prefer binding at the orthosteric site and are potential partial agonists of 5-HT1A.
In conclusion, these findings propose that every cannabinoid, regardless of whether neutral or acidic, is unique on its own in terms of its binding and function.”
https://pubmed.ncbi.nlm.nih.gov/41056675/
“Importantly, these findings indicate that every individual cannabinoids, regardless of neutral or acid congeners, is unique on its own and deserves its investigation, on its binding, function and therapeutic potential.”
https://www.sciencedirect.com/science/article/pii/S1093326325002463?via%3Dihub