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

• Main Authors: Daiana Mattoteia, Aniello Schiano Moriello, Orazio Taglialatela-Scafati, Pietro Amodeo, Luciano De Petrocellis, Giovanni Appendino, Rosa Maria Vitale, Diego Caprioglio
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Biomedicines
• Subjects: phytocannabinoids; cannabichromene; thermos-TRPs; TRPA1; α,α-dimethylheptyl effect
• Online Access: https://www.mdpi.com/2227-9059/9/8/1070

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 <i>n</i>-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 (<b>1a</b>), Δ⁸-THC (<b>6a</b>), CBG (<b>7a</b>), CBC (<b>8a</b>) and CBN (<b>9a</b>)] 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 (<b>8b</b>), the most active compound within the series, and CBC (<b>8a</b>) 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 (<b>8b</b>) as a non-covalent TRPA1-selective cannabinoid lead that is worthy of additional investigation as an analgesic and anti-inflammatory agent.