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. 2021 Aug 23;9(8):1070.
doi: 10.3390/biomedicines9081070.

The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs

Daiana Mattoteia  1 , Aniello Schiano Moriello  2   3 , Orazio Taglialatela-Scafati  4 , Pietro Amodeo  2 , Luciano De Petrocellis  2 , Giovanni Appendino  1 , Rosa Maria Vitale  2 , Diego Caprioglio  1
Affiliations

The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs

Daiana Mattoteia et al. Biomedicines. .

Abstract

The affinity of cannabinoids for their CB1 and CB2 metabotropic receptors is dramatically affected by a combination of α-branching and elongation of their alkyl substituent, a maneuver exemplified by the n-pentyl -> α,α-dimethylheptyl (DMH) swap. The effect of this change on other cannabinoid end-points is still unknown, an observation surprising since thermo-TRPs are targeted by phytocannabinoids with often sub-micromolar affinity. To fill this gap, the α,α-dimethylheptyl analogues of the five major phytocannabinoids [CBD (1a), Δ8-THC (6a), CBG (7a), CBC (8a) and CBN (9a)] were prepared by total synthesis, and their activity on thermo-TRPs (TRPV1-4, TRPM8, and TRPA1) was compared with that of one of their natural analogues. Surprisingly, the DMH chain promoted a shift in the selectivity toward TRPA1, a target involved in pain and inflammatory diseases, in all investigated compounds. A comparative study of the putative binding modes at TRPA1 between DMH-CBC (8b), the most active compound within the series, and CBC (8a) was carried out by molecular docking, allowing the rationalization of their activity in terms of structure-activity relationships. Taken together, these observations qualify DMH-CBC (8b) as a non-covalent TRPA1-selective cannabinoid lead that is worthy of additional investigation as an analgesic and anti-inflammatory agent.

Keywords: TRPA1; cannabichromene; phytocannabinoids; thermos-TRPs; α,α-dimethylheptyl effect.

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Conflict of interest statement

The authors declare no conflict of interest. The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Structures of CBD (1a), its α,α-dimethylheptyl analogue (1b), Δ9-THC (2), Δ6a,10a THC (3a), pyrahexyl (3b), CP-55.940 (4), and cannabicyclohexanol (5).
Figure 2
Figure 2
Structure of major phytocannabinoids Δ 8-THC (6a), CBG (7a), CBC (8a), and CBN (9a) and their α,α-dimethylheptyl analogues (6b–9b).
Scheme 1
Scheme 1
Synthesis of α,α-dimethylheptyl analogues of major phytocannabinoids DMH-CBD (1b), DMH-Δ8-THC (6b), DMH-CBG (7b), DMH-CBC (8b) and DMH-CBN (9b).
Figure 3
Figure 3
Representative complexes of the rTRPA1 model with (R)-CBC (colored in salmon, panel (A)), (S)-CBC (colored in tan, panel (B)), (R)-CBC-DMH (colored olive drab, panel (C)) and (S)-CBC-DMH (colored in dark green, panel (D)). A ribbon representation is used for the protein backbone and sticks for protein side chains of residues within 5 Å from the ligand, in ball & stick representation. H-bonds are shown as green sticks. Carbon atoms are painted according to receptor subunits. Sulfur, oxygen, and polar hydrogen atoms are painted yellow, red, and white, respectively.
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