Phytocannabinoids from cannabis (Cannabis sativa L.) are characterized by a linear alkyl substituent spanning one to six carbons bound to their resorcinol core, with the pentyl substitution being by far the most common one [1]. The existence of branched chain cannabinoids of the iso- and ante-iso series is, in principle, plausible from a biogenetic standpoint, since the alkylresorcinol moiety of phytocannabinoids is of ketide derivation, and branching would therefore simply require the replacement of the acetate-derived starter with one derived from a branched amino acid. However, branched phytocannabinoids of this type have only been tentatively detected as trace constituents of cannabis, largely remaining unconfirmed curiosities in its inventory of constituents [1]. Conversely, non-biogenetic branching at the benzyl carbon of the alkyl residue has played a critical role in research on cannabis and cannabinoids ever since the early synthesis of these compounds by Adams in the early forties of the past century [2]. Adams was unsuccessful in the isolation of the narcotic principle of cannabis, but the generation of a mixture of narcotic tetrahydrocannabinols from the acidic treatment of cannabidiol (CBD, Figure 1, 1a) made him correctly postulate a structure of this type for this elusive principle, whose structure was eventually established as 2 by Mechoulam two decades later [3].

In the course of these studies, Adams discovered that Δ^6a,10a-tetrahydrocannabinol (3a), an unnatural compound relatively easily available by total synthesis, could replicate most of the activity of the elusive narcotic principle of cannabis, and investigated the activity of analogues where the n-pentyl substituent of the model compound was replaced by longer, shorter, and branched alkyl groups [2]. During these studies, the remarkable potency of compounds bearing substituents on the benzyl and the homobenzyl positions of the alkyl group was discovered. One of these compounds, named pyrahexyl (3b) [4], was next developed as an incapacitating non-lethal war weapon and as anti-riot agent, but these studies terminated when the US signed the convention on the ban of chemical weapons in the early sixties [2]. A decade later, capitalizing on these observations, Pfizer chemists developed a series of ultra-potent and less lipophilic analogues of Δ⁹-tetrahydrocannabinol (2) that proved instrumental in identifying the two cannabinoid receptors, and that are still used today as a reference for cannabinoid activity, as exemplified by CP-55,940 (4). Unfortunately, these compounds are also popular designer drugs for herbal incenses (spices), as shown by cannabicyclohexanol (5), the first synthetic cannabinoid discovered in this type of product [4].

Phytocannabinoids are multi-target agents, capable of modulating a variety of end-points that includes not only metabotropic receptors (CB₁, CB₂), but also enzymes, nuclear receptors, and ionotropic receptors belonging to the family of thermo-TRPs (TRPV1-V4, TRPM8, TRPA1) [5]. In particular, thermo-TRPs represent relevant pharmacological targets in a wide array of pathological conditions ranging from pain to inflammatory and respiratory diseases [6], including those linked to COVID-19 [7]. Surprisingly, no systematic attempt has been made so far to investigate the effect of branching and elongation on the overall biological profile of phytocannabinoids. To fill this gap, we have synthesized the α,α-dimethylheptyl analogues of the five major phytocannabinoids (cannabidiol (CBD, 1a), Δ⁸-tetrahydrocannabinol (Δ⁸-THC, Figure 2, 6a) ( This biologically similar Δ⁸-analogue of 3 was used because of its major stability and ease of synthesis.), cannabigerol (CBG, 7a), cannabichromene (CBC, 8a), and cannabinol (CBN, 9a)) and compared their profile of activity against thermo-TRPs with the one of their natural analogues.