The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs
The affinity of cannabinoids for their CB<sub>1</sub> and CB<sub>2</sub> 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-dimethylhept...
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MDPI AG
2021-08-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/8/1070 |
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| author | Daiana Mattoteia Aniello Schiano Moriello Orazio Taglialatela-Scafati Pietro Amodeo Luciano De Petrocellis Giovanni Appendino Rosa Maria Vitale Diego Caprioglio |
| author_facet | Daiana Mattoteia Aniello Schiano Moriello Orazio Taglialatela-Scafati Pietro Amodeo Luciano De Petrocellis Giovanni Appendino Rosa Maria Vitale Diego Caprioglio |
| author_sort | Daiana Mattoteia |
| collection | DOAJ |
| description | The affinity of cannabinoids for their CB<sub>1</sub> and CB<sub>2</sub> 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>), Δ<sup>8</sup>-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. |
| first_indexed | 2024-03-10T08:59:18Z |
| format | Article |
| id | doaj.art-42c5d01608fb4549b402b8fd0ecf3b8b |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T08:59:18Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-42c5d01608fb4549b402b8fd0ecf3b8b2023-11-22T06:54:11ZengMDPI AGBiomedicines2227-90592021-08-0198107010.3390/biomedicines9081070The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPsDaiana Mattoteia0Aniello Schiano Moriello1Orazio Taglialatela-Scafati2Pietro Amodeo3Luciano De Petrocellis4Giovanni Appendino5Rosa Maria Vitale6Diego Caprioglio7Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, ItalyInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, ItalyDipartimento di Farmacia, Università di Napoli Federico II, Via Montesano 49, 80131 Napoli, ItalyInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, ItalyInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, ItalyDipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, ItalyInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, ItalyDipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, ItalyThe affinity of cannabinoids for their CB<sub>1</sub> and CB<sub>2</sub> 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>), Δ<sup>8</sup>-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.https://www.mdpi.com/2227-9059/9/8/1070phytocannabinoidscannabichromenethermos-TRPsTRPA1α,α-dimethylheptyl effect |
| spellingShingle | Daiana Mattoteia Aniello Schiano Moriello Orazio Taglialatela-Scafati Pietro Amodeo Luciano De Petrocellis Giovanni Appendino Rosa Maria Vitale Diego Caprioglio The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs Biomedicines phytocannabinoids cannabichromene thermos-TRPs TRPA1 α,α-dimethylheptyl effect |
| title | The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs |
| title_full | The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs |
| title_fullStr | The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs |
| title_full_unstemmed | The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs |
| title_short | The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs |
| title_sort | combined effect of branching and elongation on the bioactivity profile of phytocannabinoids part i thermo trps |
| topic | phytocannabinoids cannabichromene thermos-TRPs TRPA1 α,α-dimethylheptyl effect |
| url | https://www.mdpi.com/2227-9059/9/8/1070 |
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