Discovery of a Novel Non-Narcotic Analgesic Derived from the CL-20 Explosive: Synthesis, Pharmacology, and Target Identification of Thiowurtzine, a Potent Inhibitor of the Opioid Receptors and the Ion Channels.
| Autor: | Aguero S; Équipe ECMO, Laboratoire de Biologie Tissulaire et d'Ingénierie (LBTI), UMR5305, Université Lyon 1, Lyon 69367, France., Megy S; Équipe ECMO, Laboratoire de Biologie Tissulaire et d'Ingénierie (LBTI), UMR5305, Université Lyon 1, Lyon 69367, France., Eremina VV; Institute for Problems of Chemical and Energetic Technologies, Siberian Branch of the Russian Academy of Sciences (IPCET SB RAS), Biysk 659322, Altai Krai, Russia., Kalashnikov AI; Institute for Problems of Chemical and Energetic Technologies, Siberian Branch of the Russian Academy of Sciences (IPCET SB RAS), Biysk 659322, Altai Krai, Russia., Krylova SG; Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk 634028, Russia., Kulagina DA; Institute for Problems of Chemical and Energetic Technologies, Siberian Branch of the Russian Academy of Sciences (IPCET SB RAS), Biysk 659322, Altai Krai, Russia., Lopatina KA; Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk 634028, Russia., Fournier M; Équipe ECMO, Laboratoire de Biologie Tissulaire et d'Ingénierie (LBTI), UMR5305, Université Lyon 1, Lyon 69367, France., Povetyeva TN; Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk 634028, Russia., Vorozhtsov AB; National Research Tomsk State University, Lenin Avenue, 36, Tomsk 634050, Russia., Sysolyatin SV; Institute for Problems of Chemical and Energetic Technologies, Siberian Branch of the Russian Academy of Sciences (IPCET SB RAS), Biysk 659322, Altai Krai, Russia., Zhdanov VV; Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk 634028, Russia., Terreux R; Équipe ECMO, Laboratoire de Biologie Tissulaire et d'Ingénierie (LBTI), UMR5305, Université Lyon 1, Lyon 69367, France. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | ACS omega [ACS Omega] 2021 May 31; Vol. 6 (23), pp. 15400-15411. Date of Electronic Publication: 2021 May 31 (Print Publication: 2021). |
| DOI: | 10.1021/acsomega.1c01786 |
| Abstrakt: | The number of candidate molecules for new non-narcotic analgesics is extremely limited. Here, we report the identification of thiowurtzine, a new potent analgesic molecule with promising application in chronic pain treatment. We describe the chemical synthesis of this unique compound derived from the hexaazaisowurtzitane (CL-20) explosive molecule. Then, we use animal experiments to assess its analgesic activity in vivo upon chemical, thermal, and mechanical exposures, compared to the effect of several reference drugs. Finally, we investigate the potential receptors of thiowurtzine in order to better understand its complex mechanism of action. We use docking, molecular modeling, and molecular dynamics simulations to identify and characterize the potential targets of the drug and confirm the results of the animal experiments. Our findings finally indicate that thiowurtzine may have a complex mechanism of action by essentially targeting the mu opioid receptor, the TRPA1 ion channel, and the Ca Competing Interests: The authors declare no competing financial interest. (© 2021 The Authors. Published by American Chemical Society.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|