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Targeting Transient Receptor Potential Vanilloid 1 (TRPV1) Channel Softly: The Discovery of Passerini Adducts as a Topical Treatment for Inflammatory Skin Disorders

  • Marta Serafini
    Marta Serafini
    Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy
  • Alessia Griglio
    Alessia Griglio
    Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy
  • Silvio Aprile
    Silvio Aprile
    Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy
  • Fabio Seiti
    Fabio Seiti
    Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy
    More by Fabio Seiti
  • Cristina Travelli
    Cristina Travelli
    Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy
  • Franco Pattarino
    Franco Pattarino
    Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy
  • Giorgio Grosa
    Giorgio Grosa
    Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy
  • Giovanni Sorba
    Giovanni Sorba
    Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy
  • Armando A. Genazzani
    Armando A. Genazzani
    Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy
  • Sara Gonzalez-Rodriguez
    Sara Gonzalez-Rodriguez
    Instituto de Biología Molecular y Celular, Universitas Miguel Hernandez, Av de la Universidad s/n, 03202 Elche, Spain
  • Laura Butron
    Laura Butron
    Instituto de Biología Molecular y Celular, Universitas Miguel Hernandez, Av de la Universidad s/n, 03202 Elche, Spain
    More by Laura Butron
  • Isabel Devesa
    Isabel Devesa
    AntalGenics, SL. Ed. Quorum III, Parque Científico UMH, Av de la Universidad s/n, 03202 Elche, Spain
  • Asia Fernandez-Carvajal*
    Asia Fernandez-Carvajal
    Instituto de Biología Molecular y Celular, Universitas Miguel Hernandez, Av de la Universidad s/n, 03202 Elche, Spain
    *(A.F.-C.) Phone: +34 96 665 8454. E-mail: [email protected]
  • Tracey Pirali*
    Tracey Pirali
    Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy
    *(T.P.) Phone: +39 0321 375852. E-mail: [email protected]
  • , and 
  • Antonio Ferrer-Montiel
    Antonio Ferrer-Montiel
    Instituto de Biología Molecular y Celular, Universitas Miguel Hernandez, Av de la Universidad s/n, 03202 Elche, Spain
Cite this: J. Med. Chem. 2018, 61, 10, 4436–4455
Publication Date (Web):May 3, 2018
https://doi.org/10.1021/acs.jmedchem.8b00109
Copyright © 2018 American Chemical Society

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    Abstract

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    Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and the development of new capsaicinoids is a promising pharmacological approach in the management of skin disorders related to inflammation and pruritus. Here we report the synthesis and the evaluation of capsaicin soft drugs that undergo deactivation by the hydrolyzing activity of skin esterases. The implanting of an ester group in the lipophilic moiety of capsaicinoids by the Passerini multicomponent reaction affords both agonists and antagonists that retain transient receptor potential vanilloid 1 channel (TRPV1) modulating activity and, at the same time, are susceptible to hydrolysis. The most promising antagonist identified shows in vivo anti-nociceptive activity on pruritus and hyperalgesia without producing hyperthermia, thus validating it as novel treatment for dermatological conditions that implicate TRPV1 channel dysfunction.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b00109.

    • Molecular formula strings (CSV)

    • Concentration–response curves for selected agonists and antagonists in SH-SY5Y cells; metabolic stability in HaCaT homogenate, human plasma, liver S9, recombinant carboxylesterases (hCE1, hCE2), keratinocytes and fibroblasts homogenate; chemical stability study of compounds 17 and 36; NMR spectra of compounds 17 and 36 (PDF)

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    Cited By

    This article is cited by 28 publications.

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    2. Beatrice Riva, Alessia Griglio, Marta Serafini, Celia Cordero-Sanchez, Silvio Aprile, Rosanna Di Paola, Enrico Gugliandolo, Dalia Alansary, Isabella Biocotino, Dmitry Lim, Giorgio Grosa, Ubaldina Galli, Barbara Niemeyer, Giovanni Sorba, Pier Luigi Canonico, Salvatore Cuzzocrea, Armando A. Genazzani, Tracey Pirali. Pyrtriazoles, a Novel Class of Store-Operated Calcium Entry Modulators: Discovery, Biological Profiling, and in Vivo Proof-of-Concept Efficacy in Acute Pancreatitis. Journal of Medicinal Chemistry 2018, 61 (21) , 9756-9783. https://doi.org/10.1021/acs.jmedchem.8b01512
    3. Shun Liu, Xing Zheng, Jiao Wu, Yiqian Zeng, Xueni Wei, Anfeng Li, Xu Yao. Capsaicin derivatives: Synthesis and biological activity. Chemical Biology & Drug Design 2024, 103 (2) https://doi.org/10.1111/cbdd.14462
    4. Ying‐jie Zhu, Hu‐lin Chen, Xin‐jie Cai, Bang‐le Zhan, Xiao‐ming Liu. Naringin acts as a TRPV1 antagonist to attenuate UVB ‐induced senescence and damage in HaCaT cells. Chemical Biology & Drug Design 2024, 103 (1) https://doi.org/10.1111/cbdd.14390
    5. Jingchun Zeng, Yiqian Lu, Hui Chu, Liming Lu, Yuexuan Chen, Kaisong Ji, Yeze Lin, Jingjing Li, Shuxin Wang. Research trends and frontier hotspots of TRPV1 based on bibliometric and visualization analyses. Heliyon 2024, 10 (2) , e24153. https://doi.org/10.1016/j.heliyon.2024.e24153
    6. Miao Zhang, Yueming Ma, Xianglu Ye, Ning Zhang, Lei Pan, Bing Wang. TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases. Signal Transduction and Targeted Therapy 2023, 8 (1) https://doi.org/10.1038/s41392-023-01464-x
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    9. Chunxia Liu, Ruoyang Miao, Faisal Raza, Hai Qian, Xin Tian. Research progress and challenges of TRPV1 channel modulators as a prospective therapy for diabetic neuropathic pain. European Journal of Medicinal Chemistry 2023, 245 , 114893. https://doi.org/10.1016/j.ejmech.2022.114893
    10. Eleonóra Spekker, Tamás Körtési, László Vécsei. TRP Channels: Recent Development in Translational Research and Potential Therapeutic Targets in Migraine. International Journal of Molecular Sciences 2023, 24 (1) , 700. https://doi.org/10.3390/ijms24010700
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    12. Shujing Xu, Xujie Zhang, Yucen Tao, Xinyong Liu, Peng Zhan. Application of Multi-component Reactions in the Search of Bioactive Molecules. Mini-Reviews in Organic Chemistry 2022, 19 (8) , 894-897. https://doi.org/10.2174/1570193X19666220224101102
    13. Asia Fernández-Carvajal, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel. TRPV1 in chronic pruritus and pain: Soft modulation as a therapeutic strategy. Frontiers in Molecular Neuroscience 2022, 15 https://doi.org/10.3389/fnmol.2022.930964
    14. Antonio Ferrer-Montiel, David Cabañero, Eva Villalba-Riquelme, Gregorio Fernández-Ballester, Asia Fernandez-Carvajal. ThermoTRP Channels in Pain Sexual Dimorphism: New Insights for Drug Intervention. SSRN Electronic Journal 2022, 28 https://doi.org/10.2139/ssrn.4185823
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    16. Yu‐juan Feng, Yu‐Lin Ren, Li‐Ming Zhao, Guo‐Qiang Xue, Wen‐Hao Yu, Jia‐Qi Yang, Jun‐Wei Liu. Design, Synthesis and Biological Evaluation of Novel α‐Acyloxycarboxamide‐Based Derivatives as c‐Met Inhibitors. Chinese Journal of Chemistry 2021, 39 (8) , 2241-2250. https://doi.org/10.1002/cjoc.202100106
    17. Amanda Spring de Almeida, Laura de Barros Bernardes, Gabriela Trevisan. TRP channels in cancer pain. European Journal of Pharmacology 2021, 904 , 174185. https://doi.org/10.1016/j.ejphar.2021.174185
    18. Mengkang Gao, Yusui Wang, Lanqi Liu, Zhenrui Qiao, Lin Yan. A patent review of transient receptor potential vanilloid type 1 modulators (2014–present). Expert Opinion on Therapeutic Patents 2021, 31 (2) , 169-187. https://doi.org/10.1080/13543776.2021.1854225
    19. Mircea Iftinca, Manon Defaye, Christophe Altier. TRPV1-Targeted Drugs in Development for Human Pain Conditions. Drugs 2021, 81 (1) , 7-27. https://doi.org/10.1007/s40265-020-01429-2
    20. Marcus O. W. Grimm, Tamara Blümel, Anna A. Lauer, Daniel Janitschke, Christoph Stahlmann, Janine Mett, Viola J. Haupenthal, Anna-Maria Miederer, Barbara A. Niemeyer, Heike S. Grimm, Tobias Hartmann. The impact of capsaicinoids on APP processing in Alzheimer’s disease in SH-SY5Y cells. Scientific Reports 2020, 10 (1) https://doi.org/10.1038/s41598-020-66009-6
    21. Asia Fernández-Carvajal, Rosario González-Muñiz, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel. Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels. Expert Opinion on Investigational Drugs 2020, 29 (11) , 1209-1222. https://doi.org/10.1080/13543784.2020.1825680
    22. Gregorio Fernández-Ballester, Asia Fernández-Carvajal, Antonio Ferrer-Montiel. Targeting thermoTRP ion channels: in silico preclinical approaches and opportunities. Expert Opinion on Therapeutic Targets 2020, 24 (11) , 1079-1097. https://doi.org/10.1080/14728222.2020.1820987
    23. Linwei Zeng, Yuxin Lin, Sunliang Cui. Indole‐ N ‐Carboxylic Acids and Indole‐ N ‐Carboxamides in Organic Synthesis. Chemistry – An Asian Journal 2020, 15 (7) , 973-985. https://doi.org/10.1002/asia.201901806
    24. Silvio Aprile, Marta Serafini, Tracey Pirali. Soft drugs for dermatological applications: recent trends. Drug Discovery Today 2019, 24 (12) , 2234-2246. https://doi.org/10.1016/j.drudis.2019.08.007
    25. Marta Serafini, Enza Torre, Silvio Aprile, Alberto Massarotti, Silvia Fallarini, Tracey Pirali. Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors. Molecules 2019, 24 (10) , 1874. https://doi.org/10.3390/molecules24101874
    26. Bo Xie, Xin‐Yu Li. Inflammatory mediators causing cutaneous chronic itch in some diseases via transient receptor potential channel subfamily V member 1 and subfamily A member 1. The Journal of Dermatology 2019, 46 (3) , 177-185. https://doi.org/10.1111/1346-8138.14749
    27. Leticia Martínez-Ortega, Amalia Mira, Asia Fernandez-Carvajal, C. Reyes Mateo, Ricardo Mallavia, Alberto Falco. Development of A New Delivery System Based on Drug-Loadable Electrospun Nanofibers for Psoriasis Treatment. Pharmaceutics 2019, 11 (1) , 14. https://doi.org/10.3390/pharmaceutics11010014
    28. Sharwatie Ramsaywack, Allyson Bos, Christopher M. Vogels, Christopher A. Gray, Stephen A. Westcott. Preliminary investigations into the synthesis and antimicrobial activities of boron-containing capsaicinoids. Canadian Journal of Chemistry 2018, 96 (12) , 1065-1070. https://doi.org/10.1139/cjc-2018-0193

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