Medicinal Chemistry Endeavors around the Phytocannabinoids

Abstract

Over the past 50 years, a considerable research in medicinal chemistry has been carried out around the natural constituents of Cannabis sativa L. Following the identification of Delta9-tetrahydrocannabinol (Delta9-THC) in 1964, critical chemical modifications, e.g., variation of the side chain at C3 and the opening of the tricyclic scaffold, have led to the characterization of potent and cannabinoid receptor subtype-selective ligands. Those ligands that demonstrate high affinity for the cannabinoid receptors and good biological efficacy are still used as powerful pharmacological tools. This review summarizes past as well as recent developments in the structure-activity relationships of phytocannabinoids.

Phytocannabinoids: a unified critical inventory

“…27 The alkyl residue is a critical element for the phytocannabinoid pharmacophore, and its manipulation can lead to an increased potency compared to the natural compounds. 45 Aralkyl phytocannabinoids do not occur in Cannabis, but have an otherwise broad distribution in plants, both higher (Helichrysum, Amorpha, Glycyrrhiza and other genera) and lower (liverworts from the Radula species), with even a single report from a parasitic fungus. The aralkyl residue can be of the phenethyl-, stiryl-, or benzofuranyl type (Fig.…”

“…46 Cannabigeroids are one of the most structurally diversied class of phytocannabinoids, with structural changes being associated to the isoprenyl residue (oxidation, double bond isomerization, prenylogation), the resorcinyl core (hydroxylation or oxygenative dehydrogenation), and its substituents (esterication of the C-2 carboxylate with isoprenyl alcohols, acetylation or methylation of one of the two phenolic hydroxyls). The parent compound shows only marginal affinity for CB 1 , and, based on the SAR of D 9 -THC that emphasize the relevance of the pyrane B ring for signicant binding, 45 all the natural modications are also expected to be only marginally active on CB 1 and CB 2 . On the other hand, prenylogation increases affinity for CB 2 , 6 and a systematic evaluation of the activity on other phytocannabinoids ionotropic-or transcription factor targets should be worth evaluation.…”

“…93 D 8 -THC and D 9 -THC show a similar prole of activity on cannabinoid receptors, with D 8 -THC being only slightly less active than D 9 -THC. 45 It should, however, be interesting to evaluate the prole of the two isomers also in terms of other targets, like thermo-TRPs and transcription factors of the PPAR family, since this could provide interesting clues to clarify the role of the non-metabotropic targets in the pharmacological prole of D 9 -THC. Compounds from the D 8 series can be converted into their D 9 isomers by addition of hydrochloric acid and base-mediated dehydrohalogenation (Scheme 6).…”

The preparation of [pentane‐5,5,5‐3H3]‐abnormal‐cannabidiol

“…A number of reports have appeared in the last decade concerning the biological activity of abnormal ‐cannabidiol ( 1a ) 1, 2. This synthetic isomer of cannabidiol fails to elicit a response from either CB 1 or CB 2 receptors and lacks psychotropic activity.…”

Reaction of (−)-cis-verbenol epoxide with aromatic aldehydes over montmorillonite K10 clay

“…Compound IIIa may be regarded as a structural analog of tetrahydrocannabinol (VI). At present, tetrahydrocannabinol analogs and derivatives have attracted considerable interest due to their diverse biological activity [5][6][7].…”