• June 6, 2020

A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-Tetrahydrocannabiphorol

An Italian University Study from the University of Modena (and other contributors listed below), published in Nature.com , has found two phytocannabinoids, cannabidiphorol (CDBP) and Δ9-Tetrahydrocannabiphorol( THCP) that show a considerably higher affinity for CB1 and CB2 receptors in the brain than the normal THC and CBD associated with Cannabis Sativa L. This discovery may well be a clue as to why some strains we enjoy are so much more active in the brain than just the usual THC or CBD numbers show. – Repoman

I found it an interesting read and shows promise for both medical and recreational use. – Repoman

The full article can be found HERE

Scientific Reports volume 9, Article number: 20335 (2019) 

Abstract

(-)-Trans9-tetrahydrocannabinol (Δ9-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Δ9-THC with a longer side chain have shown cannabimimetic properties far higher than Δ9-THC itself. In the attempt to define the phytocannabinoids profile that characterizes a medicinal cannabis variety, a new phytocannabinoid with the same structure of Δ9-THC but with a seven-term alkyl side chain was identified. The natural compound was isolated and fully characterized and its stereochemical configuration was assigned by match with the same compound obtained by a stereoselective synthesis. This new phytocannabinoid has been called (-)-trans9-tetrahydrocannabiphorol (Δ9-THCP). Along with Δ9-THCP, the corresponding cannabidiol (CBD) homolog with seven-term side alkyl chain (CBDP) was also isolated and unambiguously identified by match with its synthetic counterpart. The binding activity of Δ9-THCP against human CB1 receptor in vitro (Ki = 1.2 nM) resulted similar to that of CP55940 (Ki = 0.9 nM), a potent full CB1 agonist. In the cannabinoid tetrad pharmacological test, Δ9-THCP induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating a THC-like cannabimimetic activity. The presence of this new phytocannabinoid could account for the pharmacological properties of some cannabis varieties difficult to explain by the presence of the sole Δ9-THC.

Discussion

Up to now, almost 150 phytocannabinoids have been detected in cannabis plant7,41,42, though most of them have neither been isolated nor characterized. The well-known CBD and Δ9-THC have been extensively characterized and proved to possess interesting pharmacological profiles43,44,45,46,47, thus the attention towards the biological activity of their known homologs like CBDV and Δ9-THCV has recently grown as evidenced by the increasing number of publications per year appearing on Scopus. Other homologs like those belonging to the orcinoid series are scarcely investigated likely due to their very low amount in the plant that makes their isolation very challenging. In recent years, the agricultural genetics research has made great progresses on the selection of rare strains that produce high amounts of CBDV, CBG and Δ9-THCV48,49,50, thus it would not be surprising to see in the near future cannabis varieties rich in other minor phytocannabinoids. This genetic selection would enable the production of extracts rich in a specific phytocannabinoid with a characteristic pharmacological profile. For this reason, it is important to carry out a comprehensive chemical profiling of a medicinal cannabis variety and a thorough investigation of the pharmacological activity of minor and less known phytocannabinoids.

As the pharmacological activity of Δ9-THC is particularly ascribed to its affinity for CB1 receptor, the literature suggests that the latter can be increased by elongating the alkyl side chain, which represents the main cannabinoid pharmacophoric driving force14. Therefore, taking THC as the lead compound, a series of cannabinoids have been chemically synthesized and their biological potency resulted several times higher than Δ9-THC itself15. To the best of our knowledge, naturally occurring cannabinoids with a linear alkyl side chain longer than five terms have never been detected or even putatively identified in cannabis plant. However, the cutting-edge technological platform of the Orbitrap mass spectrometry and the use of advanced analytical techniques like metabolomics can enable the discovery and identification of new compounds with a high degree of confidence even when present in traces in complex matrices42,51. In the present work, we report for the first time the isolation and full characterization of two new CBD and Δ9-THC heptyl homologs, which we named cannabidiphorol (CBDP) and Δ9-tetrahydrocannabiphorol (Δ9-THCP), respectively. These common names were derived from the traditional naming of phytocannabinoids based on the resorcinyl residue, in this case corresponding to sphaerophorol.

The biological results obtained in the in vitro binding assay indicated an affinity for CB1 receptor more than thirty-fold higher compared to the one reported for Δ9-THC in the literature14. Also, this encouraging data was supported by in vivo evaluation of the cannabimimetic activity by the tetrad test, where Δ9-THCP decreased locomotor activity and rectal temperature, induced catalepsy and produced analgesia miming the properties of full CB1 receptor agonists (Fig. 4). In particular, Δ9-THCP proved to be as active as Δ9-THC but at lower doses. In fact, the minimum THC dose used in this kind of test is 10 mg/kg, whereas Δ9-THCP resulted active at 5 mg/kg in three of the four tetrad tests. These results, accompanied by the docking data, are in line with the extensive structure-activity relationship (SAR) studies performed through the years on synthetic cannabinoids, revealing the importance of the length of the alkyl chain in position 3 on the resorcinyl moiety in modulating the ligand affinity at CB1 receptor.

Although the amount of the heptyl homologues of CBD and Δ9-THC in the FM2 variety could appear trifling, both in vitro and in vivo preliminary studies reported herein on Δ9-THCP showed a cannabimimetic activity several times higher than its pentyl homolog Δ9-THC. Moreover, it is reasonable to suppose that other cannabis varieties may contain even higher percentages of Δ9-THCP. It is also important to point out that there exists an astonishing variability of subject response to a cannabis-based therapy even with an equal Δ9-THC dose52,53,54. It is therefore possible that the psychotropic effects are due to other extremely active phytocannabinoids such as Δ9-THCP. However, up to now nobody has ever searched for this potent phytocannabinoid in medicinal cannabis varieties. In our opinion, this compound should be included in the list of the main phytocannabinoids to be determined for a correct evaluation of the pharmacological effect of the cannabis extracts administered to patients. In fact, we believe that the discovery of an extremely potent THC-like phytocannabinoid may shed light on several pharmacological effects not ascribable solely to Δ9-THC.

Ongoing studies are devoted to the investigation of the pharmacological activity of CBDP and to expand that of Δ9-THCP. It is known that CBD binds with poor affinity to both CB1 and CB2 receptors55. Therefore, the evaluation of the cannabimimetic activity of CBDP does not appear to be a high priority, although science can hold great surprises. Our current work is rather focused on testing its anti-inflammatory, anti-oxidant and anti-epileptic activity, which are typical of CBD46.

The full article can be found HERE

repoman

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